Predicting patient survival from protein stability and aggregation propensity

Amyotrophic Lateral Sclerosis (ALS), also known in America as Lou Gehrig's disease, is a fatal neurodegenerative disease that has no effective treatment. While it is well known that specific genetic mutations can cause the condition, how the changed genes produce the symptoms has previously been a mystery. A new paper in this week's PLoS Biology, the online open access journal, is able to predict ALS patient longevity to an unprecedented degree based on two properties of the protein SOD1. Jeffrey Agar and colleagues at Brandeis and Harvard Universities show that both the stickiness of SOD1 and its decreased stability accounts for 69% of patient survival data, providing strong evidence that SOD1 protein stability and its aggregation propensity are the main toxic causes of ALS.

ALS can occur spontaneously in people with no family history of the condition, but about 10% of cases run in families, and it has been shown that in about 20% of this subset of cases the underlying mutation is a change in the gene for SOD1. SOD1 is an enzyme – a biological catalyst – that neutralises potentially dangerous molecules, but ALS-causing mutant enzymes gain an unknown toxic function – i.e. the disease occurs because SOD1 does something that it doesn't do in unaffected people.

SOD1 has been shown to be mutated in at least 119 different ways in different ALS patients. Some mutations will have a more dramatic effect on SOD1 structure than others. SOD1 – like all enzymes – is a string of different amino acids in a certain pattern. Mutations that switch an amino acid for one with very different properties, or which alter an amino acid crucial for the formation of certain structural regions of the enzyme, will have a large impact on SOD1 function. Agar et al. looked at the difference in disease progression for a large population of patients with differing mutations, and found that those mutations which made SOD1 more likely to unfold from its normal structure, and those mutations that made it more likely that SOD1 would stick to other unfolded SOD1 molecules, correlated with reduced survival times post disease onset. Thus Agar et al. conclude that in people with ALS, it is the sticking together of SOD1 that is toxic.

Harvard, Columbia Researchers Make Stem Cell Breakthrough

Advance will aid search for treatments to a variety of diseases, researchers say

By CLIFFORD M MARKS

Scientists from Harvard and Columbia announced Thursday the creation of the first patient-specific stem cell line from humans afflicted with a genetic disease, a key step in the push to create therapies for a wide variety of illnesses by replacing diseased tissue with tissue generated by stem cells.

The study's two principal authors said in a press conference Wednesday that such treatments remained years away and that the more immediate impact of the disease-specific stem cells will be the ability to study disease progression and test potential treatments in a lab setting.

"We now have in the culture dish cells which have the same genetic makeup as do the ALS patients, and they are the very cells that are affected by the disease." said Columbia professor Christopher Henderson, referring to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative often called Lou Gehrig's Disease. "This provides us with the opportunity...to study these motor neurons derived from the ALS cells."

The study, which was co-authored by Henderson and Harvard professor Kevin C. Eggan, was published Thursday in the journal Science.

The age of the cell donors—82 and 89—gave the findings added significance, as some scientists had predicted using cells from older patients would complicate the creation of stem lines, according to Eggan.

"This opens the door to being able to make patient-specific, stem cell lines from diseases which affect people very late in life like Parkinson's disease or Alzheimer's disease," Eggan said.

Though the researchers originally planned to produce disease and patient-specific stem cells using the controversial practice of therapeutic cloning, which requires both a supply of human egg cells and the destruction embryos created to produce the stem cell lines, they opted instead to use a newer technique called "direct reprogramming," which was first unveiled late last year.

This method takes regular human cells—in this case skin cells—and uses viruses to reprogram them into cells that can develop into any kind of human tissue, in theory providing all the benefits of embryonic stem cells.

The current reliance on viruses renders the stem cell lines unsafe for transplantation because the process genetically modifies the reprogrammed cells. But Eggan predicted that researchers would soon fix this shortcoming with a process that instead uses chemicals to reprogram cells.

"Future research is surely going to focus on ways to replace those viruses with chemicals," he said. "And I think we'll see that in a short amount of time."

Both scientists repeatedly said that research on therapeutic cloning should not be abandoned, in large part because they said it was necessary to test the utility of reprogrammed cells against an embryonic stem cell bench mark.

"We need to compare these cells we've generated to the gold-standard cells we've generated from human embryonic stem cells," Eggan said. "Until we can do that, we won't have complete confidence."

Despite their insistence, the breakthrough and continuing difficulty in getting the egg cells required for therapeutic cloning suggests that reprogramming may provide greater hope for stem cell therapies.

Eggan said that Massachusetts law prohibiting compensation of human egg donors had stymied his lab's efforts to study the disease.

"We've now spent roughly $100,000 on advertising," Eggan said. "We've only had one woman follow through and go through the considerable effort of donating oocytes [egg cells] for research. I would characterize the number of oocytes she donated as a handful. And the results we had from those very few initial experiments were encouraging, but there's no sign of additional donors in sight."

Though the researchers expressed optimism about their ability to use the reprogrammed stem cells to study the progression of Lou Gehrig's disease and test potential treatments, a number of hurdles remain to discovering such therapies.

The researchers have not yet shown that the stem-cells-derived neurons degenerate as diseased neurons do in the human body, but they added they hope to do so in a matter of months.

In addition, the stem cells are specific to only a certain type of the disease, which afflicts less than five percent of sufferers, Eggan said. But the study authors said research on this less-common variant could have broader applications, if, as they hope, the disease mechanism is similar for most or all types of Lou Gehrig's disease despite different initial triggers in the vast majority of ALS patients.

"Our real hope is that very similar events are occurring in these sporadic patients--the 90 percent of patients in which the trigger is different," Henderson said. "Since the diseases are so similar we believe that many of the mechanisms must be similar or the same."

Protein plays Jekyll and Hyde role in Lou Gehrig's disease

Brandeis study sheds light on ALS

Waltham, MA—Amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease, is a fatal neurodegenerative disease caused by the death of motor neurons in the brain and spinal cord that control muscle movements from walking and swallowing to breathing. In a groundbreaking study this week in PLoS Biology, Brandeis and Harvard Medical School scientists report key findings about the cause and occurrence of the familial form of ALS.

For the past three years, Brandeis chemist Jeff Agar and his colleagues have studied the rare, familial form of ALS (fALS) as a window into the sporadic form of ALS, which accounts for 90 percent of all cases. Scientists discovered fifteen years ago that mutations in the gene that makes the protein, superoxide dismutase, are responsible for inherited ALS, but how these mutations cause ALS remain a mystery. Researchers believe deciphering the mechanisms at work in inherited ALS will clear the way to understanding and treating sporadic ALS, in large part because clinical symptoms are identical in both forms of the disease.

Agar's research demonstrated that fALS is caused by two synergistic properties of the protein superoxide dismutase, creating toxic levels of the protein in motor neurons. "We discovered that increased protein unfolding and the propensity of the proteins to aggregate, (to clump together) are the major factors in the familial form of ALS," explained Agar.

This propensity of proteins to unfold and clump together amounts to what scientists call a 'toxic gain of function.' Many diseases are caused by a loss of protein function, but some, like ALS, are linked to a gain of function in which a protein takes on a new role, unrelated to the one it is supposed to perform in healthy cells.

"The protein superoxide dismutase, normally a useful antioxidant, goes from Dr. Jekyll to Mr. Hyde when it clumps up," said Agar. This research indicates that protein aggregation is toxic in ALS, something that has not been proven for other neurodegenerative diseases such as Alzheimer's and Parkinson's, though researchers worldwide are studying the role of protein clumps in these conditions, as well.

Still, scientists disagree on the nature of the toxic gain of function because not all clumps are toxic, nor are they all the same size in patients with neurodegenerative disease, or healthy people, for that matter. But Agar says that large clumps cause cell death, literally exploding the thread-like axons on nerve cells that transmit impulses from the cell.

"Most people are familiar with the process of aggregation, which is what happens when you cook an egg. A fluid (the egg white) is full of proteins that are free to move about. Upon cooking, these proteins unfold and clump together. When this happens inside a cell, especially inside the long, narrow, tubes that connect neurons (axons), the cells essentially choke because they can't move proteins and nutrients to where they are needed. The loss of motor neurons then results in the death of ALS patients."

The next step, said Agar, is to develop drugs that target key proteins and prevent them from clumping together. "Our study used data from innumerous ALS researchers, and the field has been working toward this discovery for some time. My hope is that if our findings are validated by other research groups, molecules that prevent aggregation will be developed and used to treat ALS. We hope to contribute to this process and have initiated the lengthy process of developing such molecules in collaboration with the laboratories of Greg Pestko and Dagmar Ringe here at Brandeis."

Umbilical cord blood cell transplants may help ALS patients

Moderate dose proves most effective in mouse model

Tampa, FL (June 24, 2008) – A study at the University of South Florida has shown that transplants of mononuclear human umbilical cord blood (MNChUCB) cells may help patients suffering from Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease. A disease in which the motor neurons in the spinal cord and brain degenerate, ALS leaves its victims with progressive muscle weakness, paralysis and, finally, respiratory failure three to five years after diagnosis.

In this study, USF researchers transplanted human umbilical cord blood (HUCB) cells into mouse models with ALS. Cells were transplanted at three different dose strength levels -- low, moderate and high -- to determine the degree to which dose levels of transplanted cells might delay disease symptom progression and increase lifespan. In results published today online at PloS ONE (Public Library of Science), researchers determined that the moderate-strength dose of HUCB cells was most effective in increasing lifespan and reducing disease progression.

"Our results demonstrate that treatment for ALS with an appropriate dose of MNC hUBC cells may provide a neuroprotective effect for motor neurons through active involvement of these cells in modulating the host immune inflammatory system response," said the study's lead author Svitlana Garbuzova-Davis, PhD, DSc, of the Center of Excellence for Aging and Brain Repair at USF.

According to the research team, modulating immune and inflammatory effectors with HUCB cells could have a protective effect on dying motor neurons. The team had previously shown that hUBC cell transplants reduced inflammation and provided neuroprotection in models of stroke and Alzheimer's disease.

"This preclinical study indicates that MNC hUBC cells may protect motor neurons by inhibiting an immune inflammatory response by decreasing pro-inflammatory cytokines, signaling proteins in the brain and spinal cord that play a role in immune response," Garbuzova-Davis and colleagues wrote. "Proinflammatory cytokines may be indirect mediators for glial cells' contribution to motoneuron death and the decrease in these cytokines might be due to a reduction of activated microglia, the cells that form active immune defense in the central nervous system."

The research team noted, however, that the mechanism underlying the beneficial effect of hUBC cells for repairing diseased motor neurons in ALS still needs more clarification.

Suggesting that 'more is not better,' it was the moderate, not the high, dose of hUBC cells that proved most effective. Researchers speculated that the high dose may have been less effective because it induced an immunological conflict within the mouse model.

"Future studies should look at multiple injections of smaller doses over time, in order to help translate this research to clinical trials," according to co-author Paul R. Sanberg, PhD, DSc, director of the Center.

"Developing an effective treatment for ALS is complicated by the diffuse nature of motor neuron death," concluded Garbuzova-Davis. "However, cell therapy may offer a promising new treatment."

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The other co-authors of the study were Cyndy Davis Sanberg and Nicole Kuzmin-Nichols of Saneron CCELL Therapeutics, Inc., and Alison E. Willing, Carmelina Gemma, Paula C. Bickford, Christina Miller, and Robert Rossi from USF.

Lou Gehrig's Disease Protein Found Throughout Brain, Suggesting Effects Beyond Motor Neurons

PHILADELPHIA, June 16 (AScribe Newswire) -- Two years ago researchers at the University of Pennsylvania School of Medicine discovered that misfolded proteins called TDP-43 accumulated in the motor areas of the brains of patients with amyotropic lateral sclerosis (ALS), or Lou Gehrig's disease. Now, the same group has shown that TDP-43 accumulates throughout the brain, suggesting ALS has broader neurological effects than previously appreciated and treatments need to take into account more than motor neuron areas. Their article appeared in last month's issue of the Archives of Neurology.

"The primary implication for ALS patients is that we have identified a molecular target for new therapies," says co-author John Q. Trojanowski, MD, PhD, Director of Penn's Institute on Aging. "The other implication is that new therapies for ALS now need to go beyond treating only motor neurons."

Traditionally, ALS has been diagnosed based on muscle weakness and neurodegeneration of the upper and lower motor neurons that extend from the motor cortex to the spinal cord and brainstem motor neurons, which directly innervate voluntary muscles. For example, if you want to wiggle your big toe, the signal travels from the motor neuron in the cortex at the top of your head to a synapse on the lower spinal cord motor neurons in the lower back, which, in turn transmit the "wiggle" command by sending a signal to the muscles that move your big toe. Patients with ALS cannot wiggle their big toe or complete other voluntary muscle movements, including those carried out by their other extremities and eventually, by the diaphragm that moves air in and of their lungs.

The study was conducted by examining post-mortem brain tissue of 31 ALS patients. The accumulation of TDP-43 was imaged by detecting TDP-43 with an antibody specific for this protein. TDP-43 pathology was observed not only in the areas of the brain and spinal cord that control voluntary movements, as expected, but also in regions of the brain that involve cognition, executive functioning, memory, and involuntary muscle control. TDP-43 pathology was not observed in any of the controls that did not have ALS.

The pathological TDP-43 observed in ALS brains is different in two ways from normal TDP-43 that is found in most cells. The ALS-associated TDP-43 includes fragments of normal TDP-43 as well as other abnormally modified forms of TDP-43, and it is located in the cytoplasm of neurons; whereas, normal TDP-43 is found almost exclusively in the cell nucleus. In ALS, the pathological TDP-43 accumulates in large "globs," mainly in cell bodies.

"Our observation of TDP-43 in the brains of ALS patients suggests that ALS and two other neurodegenerative diseases called ALS- PLUS [ALS with cognitive impairments] and FTLD [frontotemporal lobar disease] may all have the same underlying molecular pathology involving abnormal TDP-43," says Trojanowski. "This constitutes a paradigm shift in the way we think about these diseases."

Current research is focused on understanding the basic biology of TDP-43 in cell culture systems. The research team is now trying to find out whether pathological TDP-43 causes nerve cells to lose their normal function or if they take on a toxic function. "The over-riding goal that drives our work is helping ALS patients," says Trojanowski.

Felix Geser, of Penn, was lead author on this study. Linda Wong, Maria Martinez-Lage, Lauren Elman, Leo McCluskey, Sharon Xie, and Virginia Lee, all of Penn, and Nicholas Brandmeir, of Albany Medical College, Albany, NY were co-authors. This research was supported by grants from the National Institute on Aging.

ABOUT PENN MEDICINE

PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals - its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center - a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

Vancouver researchers pioneer safe pathway to slow ALS using stem cells

A unique pilot study has established a safe pathway for using bone-marrow stem cells to slow down and potentially treat Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease without cure.

The study, published in the journal, Muscle & Nerve and led by Dr. Neil Cashman, professor of neurology at The University of British Columbia and director of the ALS program at Vancouver Coastal Health and VCH Research Institute, tested the use of a growth factor stimulant in ALS patients and found that bone-marrow stem cells became activated with no adverse effects to patients.

“Our idea was to use a growth factor stimulant to increase the number of circulating stem cells from within the body’s bone marrow where they would have the potential to travel to the site of injury and begin repair, slowing down the progression of ALS,” says Cashman, who also holds the Canada Research Chair in Neurodegeneration and Protein Misfolding Diseases at UBC and is a member of the Brain Research Centre at UBC Hospital.

“This pathway, if one day successful, may provide a new therapy that will avoid the ethical debate surrounding embryonic stem cells,” says Cashman.

Growth factors are proteins that can stimulate cell division. They occur naturally in the human body and can also be developed in a laboratory. Stem cells serve as a “repair system” in the human body and have the potential to develop and divide into many different cell types.

“The project was complex because growth factors have the potential to activate the wrong cells in the brain and spinal cord, which could be harmful to ALS patients” says Cashman.

The researchers identified Granulocyte Colony Stimulating Factor (G-CSF) as the safest possible growth factor to use. They then conducted the pilot trial to establish safety and measure stem cell mobilization.

“We were able to measure a prominent effect on stem cell mobilization and found no adverse effects in the patients,” said Cashman. “There have been many misgivings in using stem cell stimulators in ALS patients but now we know we can safely do this. This is an important first step in providing a new treatment for ALS.”

The research team is now developing a larger scale multicentre trial to look at therapeutic effect. This trial is at least one year away from beginning.

ALS is a progressive and ultimately fatal neurodegenerative disease that produces weakness, atrophy – partial or complete wasting away of a part of the body, and spasticity – continuous contracting of certain muscles. It results from progressive degeneration of motor neurons in the brain, brainstem, and spinal cord. There is no cure for ALS and to date the only registered pharmacological treatment is riluzole, which slows the progression of the disease on average by 10-15 per cent. New effective therapies are greatly needed to slow or halt this disease.

The Webster Foundation in Montreal through the VGH & UBC Hospital Foundation in Vancouver, as well as the Temerty Family Foundation in Toronto provided funding for this study. The co-authors include Dr. Andy Eisen (senior author), professor Emeritus, Neurology, University of British Columbia and former director Vancouver Coastal Health ALS program; and Dr. Charles Krieger, associate professor of kinesiology, Simon Fraser University, professor, neurology, clinical associate professor, Neurology, University of British Columbia, and clinician researcher VCH ALS program.

VCHRI is the research body of Vancouver Coastal Health Authority. In academic partnership with UBC, the institute advances health research and innovation across B.C., Canada, and beyond. www.vchri.ca

The Faculty of Medicine at UBC provides innovative programs in the health and life sciences, teaching students at the undergraduate, graduate and postgraduate levels, and generates more than $200 million in research funding each year.

The Brain Research Centre at UBC Hospital is a multidisciplinary centre dedicated to improving understanding and finding new treatments for brain diseases. The centre is a partnership of the University of British Columbia and Vancouver Coastal Health Research Institute.

Support cells modify Lou Gehrig's Disease

By Deanna Chieco

Glial cells, the supporting cells of the nervous system, are present everywhere in your brain and spinal cord and help with communication between neurons.

Despite their supportive role in the healthy nervous system, these glial cells can undergo functional changes after a brain injury or during illness that make it harder for the nervous system to heal.

A group of Hopkins researchers led by Nicholas Maragakis, a neurologist at the School of Medicine, examined the role of glial cells in the neurodegenerative disease amyotrophic lateral sclerosis, known as ALS or Lou Gehrig's Disease.

ALS involves the progressive degeneration of motor neurons, which transmit signals from the brain that tell muscles what to do, and eventually leads to weakness, paralysis and death.

The researchers examined how the growth or proliferation of astrocytes, a type of glial cell found throughout the central nervous system, could play a role in the cause of ALS.

Following an injury, astrocytes undergo a process called reactive astrogliosis, in which they lose their normal functioning and exhibit altered gene expression.

In a healthy nervous system, astrocytes play a supporting role which consists of regulating neurotransmitter and ion uptake as well as preventing toxins in the blood from reaching the brain.

However, if astrocytes become reactive, they can lead to the death of their neighboring neurons because of the loss of vital functions.

Working from previous evidence that reactive astrogliosis was important in neurodegenerative disorders, this group of researchers investigated a connection between the proliferation of these reactive astrocytes and ALS.

They used two mouse models that were genetically modified to express either an acute or chronic form of motor neuron disease. Markers were used to label dividing astrocytes in tissue sections for each mouse model. Astrocytes and motor neurons in the lower region of the spinal cord were the main area of focus.

The acute model represents the immediate cellular changes following a traumatic brain or spinal cord injury. In this model, they found that astrocyte proliferation was reduced in the disease model as compared to a wild-type mouse.

However, if these proliferating astrocytes were ablated, or removed, there was not a significant decrease in the number of reactive glial cells.

They concluded that proliferating astrocytes were not a large component of the reactive astrocytes contributing to acute motor neuron disease.

The chronic mouse model, which implies a slower onset and progression of disease-like symptoms, is more representative of ALS. In this case, the number of proliferating astrocytes was also reduced but found not to be the main contributor to reactive astrogliosis.

Additionally, if the proliferating astrocytes were ablated, the disease-like symptoms were retained, indicating that cell death of motor neurons was still occurring.

In each of these models, there was an increase in the number of astrocytes present, though they may not have been actively dividing at the time.

For a chronic disease like ALS, if large numbers of astrocytes proliferate over a long period of time, there could still be a significant effect on astrogliosis.

Though the researchers did not find improved symptoms if proliferating astrocytes were ablated, they were able to better define the role of these astrocytes in terms of nervous system injury and degeneration.

They determined that proliferating astrocytes are a relatively small contributor to the symptoms of the disease, but that they are in fact present in reactive astrogliosis.

Scientists Develop Yeast-Based Genetic Screen for Protein Linked to ALS and FTD

Researchers from the University of Pennsylvania School of Medicine have developed a yeast model that can screen for proteins that combat certain neurodegenerative diseases.

Past research has found a number of mutations in a disease protein called TDP-43, which is implicated in amyotrophic lateral sclerosis (ALS) and certain types of frontotemporal dementia (FTD), the scientists comment.

Based on these studies suggesting TDP-43 as a cause of ALS and FTD, the Penn team created a yeast model to express this protein. They found that TDP-43 formed clumps in the yeast model in the same way that it does in human nerve cells. They also identified particular segments of the mutated TDP-43 protein that cause it to aggregate and which parts cause it to be toxic.

The scientists were able to replicate the clumping process of proteins, which takes decades in humans, within hours in yeast cells. This allows for visualization of the clumping, rapid genetic screening to identify proteins that can reverse the harmful effects of the disease protein, and testing molecules that could eliminate or prevent clumping.

The Penn team is now pursuing drug screens with their TDP-43 model. The current study also involved scientists from Johns Hopkins and the Whitehead Institute for Biomedical Research. Findings are published in this weeks advance online issue of the Proceedings of the National Academy of Sciences.

Formaldehyde Exposure May Increase Risk Of ALS Disease

People exposed to formaldehyde - a chemical used mostly in household products - have increased risk for developing amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.

Researchers from Harvard School of Public Health examined the link between ALS and 12 types of chemicals. Study was initially focused on affect of pesticides and herbicides, but later they found formaldehyde to be increasing the risk for developing the disease.

The study examined 1100 people who were questioned about the levels of formaldehyde exposure. The study began in 1982 and followed the participants during 15 years. Those who were exposed to the chemical showed to be 34% more likely to develop amyotrophic lateral sclerosis than those exposed to other chemicals.

People with certain jobs - 'beautician, pharmacist, mortician, chemist, lab technician, dentist, fireman, photographer, printer, nurse, doctor and veterinarian' - are also at 30% more likely to develop ALS than people with other professions, because they are being exposed to chemicals constantly.

Formaldehyde is a chemical widely used in wood products. It's used in press fabrics, glues, shampoos, and cosmetics. Formaldehyde is also used in laboratories and mortuaries for preserving tissues and for disinfecting.

Amyotrophic lateral sclerosis is a disease also named as Lou Gehrig's disease, because in 1941 Lou Gehrig - New York Yankees baseball player - died of ALS. The disease kills nerve cells in brain and spinal cord called motor neurons. These cells are responsible for muscle movements. Annually, ALS affects about 5600 people in US.

Chemical Exposure May Increase Risk Of ALS, Study Shows

ScienceDaily (Apr. 17, 2008) — Preliminary results show that a common environmental chemical may increase the risk of developing amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, according to new research.

The study was based on the Cancer Prevention Study II of the American Cancer Society. Over one million people were asked to report their exposure to 12 types of chemicals. The participants were followed for 15 years, and the number of people who died during that time of ALS was tracked. A total of 617 men and 539 women died from ALS during the study.

Researchers found no significant link between ALS and exposure to most chemicals, including pesticides and herbicides. People who reported that they had regular exposure to formaldehyde, however, were 34 percent more likely to develop ALS than those with no exposure to formaldehyde.

"Although this finding could well be a chance observation, it merits further investigation, particularly because people with longer exposure to formaldehyde had a greater risk of developing ALS than those with shorter exposures," said study author Marc Weisskopf, PhD, of Harvard University in Boston. "People who reported 10 or more years of exposure were almost four times as likely to develop ALS as those with no exposure."

Weisskopf said the results are preliminary and more research needs to be done to test the results. "This finding was somewhat surprising, because formaldehyde has not been raised as an issue in ALS before," he said.

Formaldehyde is used in particle board and other wood products, permanent press fabrics, glues, and other household products, such as cosmetics and shampoo. It is also used as a preservative in medical laboratories and mortuaries, and as an industrial disinfectant.

Weisskopf noted that the participants were asked about their exposure to formaldehyde and other chemicals in 1982. In 1987, formaldehyde was classified as a probable human carcinogen at high exposure levels by the U.S. Environmental Protection Agency in 1987.

"Exposure since then has generally decreased, but it certainly isn't gone," he said.

This research was presented at the American Academy of Neurology 60th Anniversary Annual Meeting in Chicago, April 16, 2008.

The study was supported by a grant from the U.S. Department of Defense.

Leaky blood vessels open up nerve cells to toxic assault in Lou Gehrig's disease

Leaky blood vessels that lose their ability to protect the spinal cord from toxins may play a role in the development of amyotrophic lateral sclerosis, better known as ALS or Lou Gehrigs disease, according to research published in the April issue of Nature Neuroscience.

The results mark the first time that scientists have witnessed molecular changes occurring long before key nerve cells start dying. The unexpected finding opens up a new front in studies of ALS, a disease in which motor neurons in the spinal cord die off for unknown reasons, resulting in dramatically weakened muscles. Patients lose their strength, their ability to move or swallow, and eventually lose their ability even to breathe. Most patients live only a few years after diagnosis.

We believe these changes contribute to or possibly initiate the onset of ALS, said lead author Berislav Zlokovic, M.D., Ph.D., of the University of Rochester Medical Center. Its clear that these changes occur before the loss of neurons, and its well known that the types of changes we are seeing certainly injure or kill these types of cells, which are extremely sensitive to their biochemical environment.

The results, discovered by studying mutant mice that have an inherited form of the disease, were made by a collaboration of neuroscientists from the University of Rochester Medical Center working together with a team of ALS experts from the University of California at San Diego. Zlokovic, a pioneer in learning how the bodys vascular system plays a role in neurodegenerative diseases like Alzheimers disease and ALS, led the team, and the first author is post-doctoral researcher Zhihui Zhong, Ph.D.

While its unlikely the new findings will help ALS patients immediately, the results open up a new and unexpected way to think about the disease. Zlokovics team is currently testing in the laboratory a compound that may help seal up leaky vessels and protect the neurons targeted by ALS.

The team studied mice with a mutation in a gene for superoxide dismutase 1 (SOD-1), which in healthy people and mice plays an important role keeping cells safe from damaging molecules known as free radicals. Scientists estimate that SOD-1 mutations play a role in a small number of cases of ALS overall in people, about one-quarter of the 10 percent or so of cases that are inherited. But those cases provide a unique window to study the diseases initial steps.

In the Nature Neuroscience paper, the group from Rochesters Center for Neurodegenerative and Vascular Brain Disorders and UCSD showed that a breakdown in the natural barrier between the blood and the spinal cord breaks down early on in mice destined to get ALS, long before nerve cells appear sick or die.

In this work, the team showed that the barrier between the blood and the spinal cord weakens in all three types of genetically based ALS cases that involve SOD-1 mutations, allowing toxic substances to flood into the spinal cord and directly affect neurons.

That barrier is crucial for the health of our central nervous system, which is treated like the inner sanctum of the body. Like a high-performance race car that demands a choice fuel, our neurons work well only if the chemical environment in the brain and spinal cord is precisely maintained within a strict, narrow set of conditions.

To maintain that select environment, the body has strict barriers or gateways for substances entering or exiting the central nervous system. Blood vessels run through our brain and spinal cord and supply oxygen and other nutrients, and the lining of those blood vessels constitutes a biochemical barrier to protect the central nervous system from toxins, inflammatory cells, red blood cells, blood products, and a variety of other potential toxic insults.

The barrier between the blood and the spinal cord isnt some stand-alone structure that keeps all substances away from the spinal cord. Rather, the word barrier describes an elaborate molecular lattice that lines the insides of the blood vessels that weave throughout the spinal cord. The lattice controls which molecules can cross from the blood to the neurons in the spinal cord, and which cannot. Its a bit like netting with very small openings that line the inside of blood vessels.

Oxygen and many nutrients get the OK to pass through the barrier in measured amounts. And the barrier readily accepts waste products from the spinal cord, transporting them away from the central nervous system and eventually out of the body. But the netting should be taut and should bar substances in the blood that have no business being near neurons.

The team found that a SOD-1 mutation disrupted key building blocks in the barrier. Essentially, the mutations loosened the lattice, creating bigger holes in the barrier that allowed molecular interlopers to pass from the blood to the spinal cord.

Mice with the mutation had lower levels of three types of tight junction proteins that are key components of the barrier: ZO-1, occludin and claudin-5. In mice just two months old, the numbers of those important tight junction proteins in the linings of blood vessels were reduced by about half, by 40 to 60 percent, allowing the lattice to loosen abnormally.

The weakened barrier brought about several problems. Neurons were exposed directly to biochemical byproducts of hemoglobin, which forms reactive oxygen molecules that injure neurons. Where the barrier had weakened, tiny hemorrhages dotted the spinal column. The smallest blood vessels crucial to nerve health shrunk: Mice with the mutation had total capillary length in the spinal cord 10 to 15 percent less than healthy mice, and their blood flow in the spinal cord was reduced by 30 to 45 percent.

Scientists must investigate whether the same processes happen in forms of ALS that are not inherited. Zlokovic notes that from what is known so far, the disease progresses exactly in inherited forms and forms that are not inherited.

The vascular system is crucial to health its how oxygen and other nutrients are delivered to cells, and how toxins are removed, said Zlokovic, who is professor of Neurosurgery and Neurology and director of the Center for Neurodegenerative and Vascular Brain Disorders. Any damage to the vascular system is a serious threat to the organism. Its clear now that the vascular system is certainly involved in the development of ALS.

Zlokovic first began doing research on the disease in 2004, when a former classmate from medical school who had been diagnosed with ALS and was looking for new treatments contacted him. By the time his friend died two years later, Zlokovic was well underway in studies investigating the possible role of the vascular system.

During the last 15 years, Zlokovic has pioneered the view that the vascular system plays a central role in many neurodegenerative diseases. He has found that a breakdown in the barriers between the blood and the central nervous system may be at the root of diseases like Alzheimers. In January, Zlokovic reviewed the evidence for involvement of the barrier in diseases like Alzheimers, ALS, and multiple sclerosis in a 24-page review in Neuron.

###

The research team included Zlokovic, Zhong, and Don Cleveland, Ph.D., a widely recognized ALS expert who is a researcher at the University of California at San Diego. Previously, Cleveland has shown that cells besides neurons in the spinal cord, such as astrocytes and microglia, have an effect on the course of the disease.

Other authors of the paper include Rashid Deane, Ph.D., associate professor; medical student Zarina Ali; technical associate Margaret Parisi; Kerry OBanion, M.D., Ph.D., associate professor of Neurobiology and Anatomy; graduate student Yuriy Shapovalov; former student Konstantin Stojanovic; post-doctoral researcher Abhay Sagare, Ph.D.; and post-doctoral fellow Sverine Boille of UCSD. The National Institutes of Health and the Muscular Dystrophy Association funded the work.

New Gene Responsible For Lou Gehrig's Disease Identified

ScienceDaily (Mar. 31, 2008) — A team of Canadian and French researchers has identified a novel gene responsible for a significant fraction of ALS (sporadic amyotrophic lateral sclerosis) cases. ALS is commonly referred to as Lou Gehrig's disease, an incurable neuromuscular disorder that affects motor neurons and leads to paralysis and death within one to five years.

The team identified several genetic mutations in the TDP-43 gene by studying ALS patients from France and Quebec. They established TDP-43 as the gene responsible for up to five percent of the ALS patients.

Published in Nature Genetics, the study on 200 human subjects with ALS was led by Doctors Guy Rouleau, Edor Kabashi, Paul Valdmanis of the Research Centre of the Centre hospitalier de l'Université de Montréal (CRCHUM).

The breakthrough is the result of teamwork with peers from the Waterloo and Laval universities in Canada and the Fédération des maladies du système nerveux and the Institute of Biology (Unité de Neurologie Comportementale et Dégénérative) in France.

Building on past studies

In 1993, Dr. Rouleau and his team also helped identify "superoxide dismutase" as the gene that causes the disease in 10 to 20 percent of all familial cases of ALS. This cornerstone study led to development of several mouse and rat models of ALS that closely resemble the motor neuron disorder observed in ALS patients. These models have been very useful to study molecular and cellular mechanisms of disease and to test treatments for ALS.

TDP-43's normal function is to bind and splice RNA. Two years ago, a team from the University of Pennsylvania discovered TDP-43 in abnormal protein clumps, referred to as aggregates, in motor neurons of ALS patients. However, it was not certain whether TDP-43 causes motor neuron disease or is just a pathological marker.

"The identification of additional mutations in TDP-43 in other ALS patients will confirm that this gene is a prominent cause of this type of disorder," said Dr. Rouleau, director of the Sainte-Justine Hospital Research Centre. "Animal models over-expressing the mutations identified in this study will provide crucial insight into how TDP-43 aggregate and ultimately kill motor neurons."

"This discovery is a step towards the development of therapies for people suffering from this terrible disease and possibly other neurodegenerative diseases," said Dr. Kabashi.

Drs. Rouleau and Kabashi are financially supported by the Canadian Institutes of Health Research (CIHR) and ALS Canada. Their research was also funded by the Muscular Dystrophy Association and the ALS Association.

Toxic organophosphates appear to contribute to motor neuron disease

Motor neuron disease is a rare, devastating illness in which nerve cells that carry brain signals to muscles gradually deteriorate.

One form of it, Lou Gehrig's disease or ALS (amyotrophic lateral sclerosis), is familiar to the public in the lives of scientist Stephen Hawking and Morrie Schwartz, about whom Mitch Albom's "Tuesdays with Morrie" was written.

For most MND patients, the cause is unknown. Figuring out why these people develop the disease, which causes muscles to weaken, atrophy and cease to function, is an important step in developing therapies to treat or prevent motor neuron disease.

Now a team of University of Michigan scientists has gotten a step closer:

• They have discovered mutations in one key gene (neuropathy target esterase, or NTE) that cause a previously unknown type of inherited motor neuron disease.
  
• The discovery paves the way for better diagnosis and research on treatments.
  Most intriguing, the scientists found the mutations caused changes in a protein already known to be involved when people develop neurologic disorders as a result of exposure to toxic organophosphates-chemicals commonly used in solvents and insecticides and also as "nerve gas" agents. This discovery points to a new lead in the search to understand MND.
  
• "We speculate there may be gene-environment interactions that cause some forms of motor neuron disease," says John K. Fink, M.D., professor of neurology at the U-M Medical School and senior author of the new study, which appears in the March issue of the American Journal of Human Genetics. He also is a researcher at the VA Ann Arbor Healthcare System.
  

"Our findings support the possibility that toxic organophosphates contribute to motor neuron disease in genetically vulnerable people," says Fink. He believes the results suggest that altered activity of the gene found in patients in the study may also contribute to other motor neuron disorders, possibly including ALS. Motor neuron disease affects five per 100,000 people.

The findings are an exciting first step in uncovering a possible link between the environment and motor neuron disease, says Shirley Rainier, a research assistant professor at the U-M Department of Neurology and the first author of the study. "Why does one person in a family get it, and another doesn't""

Piecing together a puzzle

In the 1930s, an estimated 50,000 people in the U.S. became lame or otherwise neurologically affected by neurotoxic organophosphates when they drank a contaminated batch of "ginger jake," an alcohol-containing potion that was legal during Prohibition.

Ginger jake suppliers substituted a lubricating oil for the oil usually used, castor bean oil, when castor bean prices went up. A 2003 article in the New Yorker detailed the sad results, which led bands like the Mississippi Sheiks to write songs about the "ginger jake blues."

More recently, there have been incidents in Fiji, India and Africa when accidental consumption of oils containing neurotoxic organophosphates (instead of cooking oil) caused death or nerve damage for tens of thousands of people. Although scientists don't yet know the exact manner in which toxic organophosphate exposure leads to progressive and permanent nerve damage, they have learned that this process involves disturbance of an enzyme, NTE, contained within nerves.

Fink examined members of two families who had progressive weakness and spasticity (tightness) in their legs, as well as muscle atrophy in their hands, shins and feet. James Albers, M.D., Ph.D., a U-M professor of neurology and an expert in neuromuscular disorders, studied nerve and motor function. Rainier performed genetic studies and determined that the gene for the condition was on a region of chromosome 19.

Mark Leppert, Ph.D., co-chair of human genetics at the University of Utah, and his team performed genetic analysis that confirmed this location and excluded other areas in the genome. Among the many genes in this region of chromosome 19, one gene stood out as particularly likely: the gene that encodes for NTE. Because of its known role in organophosphate-induced neurological disease, the NTE gene was considered an important candidate gene and was studied immediately.

Analysis showed that the affected people in each family had NTE gene mutations. These mutations altered a critical part of the NTE protein called the esterase domain. Fink has named the inherited condition "NTE motor neuron disease." It begins in childhood and progresses slowly, with symptoms of weakness and spasticity in the legs and muscle atrophy in the hands and lower legs.

Next, Fink and his team want to learn if mutations in the NTE gene happen in other types of motor neuron disease such as ALS, and if the mutations make a person more vulnerable to neurological damage from organophosphate exposure. Fink's lab is currently using fruit flies as a model to study the NTE mutations, with the goal of finding treatments for people with motor neuron disease.

Study shows ALS aggregates are composed of only one protein

Washington, Mar 23 (ANI): A new study has provided a big clue to help fight amyotrophic lateral sclerosis (ALS), by discovering that the dense protein aggregates that contribute to the nerve decay of ALS are composed of just one protein - superoxide dismutase (SOD1).

Usually familial ALS is characterised by the aggregation of mutated SOD1, a protein that normally protects cells from free radical damage. However, the exact composition of these aggregates is not clear. Thus, identifying the other proteins present and if they are modified in any way could help answer how they form and why they are so toxic.

The study, led by Julian Whitelegge, made use of mass spectrometry to uncover the components of these aggregates and to their surprise the researchers discovered that they were composed almost entirely of SOD1.

However, some samples contained trace amounts of random abundant nerve proteins that likely got there by happenstance.

Besides, after analysing ALS mouse spinal cords, it was shown that almost all the SOD1 was fully intact protein and not partial or damaged fragments. Similarly, no evidence was found for extensive chemical modifications (that were not readily removed by DTT treatment).

Though there are many questions still remaining about these aggregates, the study has given provided a starting point, indicating that aggregation is an intrinsic property of mutant SOD1, just like the amyloid plaques associated with Alzheimers.

ALS Aggregates Are Composed of Only One Protein

Researchers have provided a big new clue to help combat amyotrophic lateral sclerosis (ALS), deciphering that the dense protein aggregates that contribute to the nerve decay of ALS are composed of just one protein: superoxide dismutase (SOD1).

While the aggregation of mutated SOD1, a protein that normally protects cells from free radical damage, is a tell-tale sign of familial ALS, the exact composition of these aggregates has been unclear. Identifying the other proteins present and if they are modified in some way could help answer how they form and why they are so toxic.

In a study appearing online in JBC March 21, Julian Whitelegge and colleagues Joan S. Valentine and David Borchelt used mass spectrometry to uncover the components of these aggregates and discovered, somewhat surprisingly, that they were composed almost entirely of SOD1 (some samples contained trace amounts of random abundant nerve proteins that likely got there by happenstance).

In addition, their analysis of ALS mouse spinal cords showed almost all the SOD1 was fully intact protein and not partial or damaged fragments. Likewise, the researchers did not find evidence for extensive chemical modifications (that were not readily removed by DTT treatment).

While many questions about these aggregates still remain, this study has given scientists a starting point, suggesting that aggregation is an intrinsic property of mutant SOD1, very much like the amyloid plaques associated with Alzheimer’s.

Motor Neuron Disease and Toxic Exposure: Possible Link?

University of Michigan scientists have found that people with a form of inherited motor neuron disease have abnormalities in the same gene that appears to be affected in people who suffer nerve damage after exposure to harmful amounts of organophosphates, chemicals used in insecticides and nerve gas.

Motor neuron disease is a rare, devastating illness in which nerve cells that carry brain signals to muscles gradually deteriorate. One form of it, Lou Gehrig’s disease or ALS (amyotrophic lateral sclerosis), is familiar to the public in the lives of scientist Stephen Hawking and Morrie Schwartz, about whom Mitch Albom’s “Tuesdays with Morrie” was written.

For most MND patients, the cause is unknown. Figuring out why these people develop the disease, which causes muscles to weaken, atrophy and cease to function, is an important step in developing therapies to treat or prevent motor neuron disease.

Now a team of University of Michigan scientists has gotten a step closer:
* They have discovered mutations in one key gene (neuropathy target esterase, or NTE) that cause a previously unknown type of inherited motor neuron disease.
* The discovery paves the way for better diagnosis and research on treatments.
* Most intriguing, the scientists found the mutations caused changes in a protein already known to be involved when people develop neurologic disorders as a result of exposure to toxic organophosphates—chemicals commonly used in solvents and insecticides and also as “nerve gas” agents. This discovery points to a new lead in the search to understand MND.

“We speculate there may be gene-environment interactions that cause some forms of motor neuron disease,” says John K. Fink, M.D., professor of neurology at the U-M Medical School and senior author of the new study, which appears in the March issue of the American Journal of Human Genetics. He also is a researcher at the VA Ann Arbor Healthcare System.

“Our findings support the possibility that toxic organophosphates contribute to motor neuron disease in genetically vulnerable people,” says Fink. He believes the results suggest that altered activity of the gene found in patients in the study may also contribute to other motor neuron disorders, possibly including ALS. Motor neuron disease affects five per 100,000 people.

The findings are an exciting first step in uncovering a possible link between the environment and motor neuron disease, says Shirley Rainier, a research assistant professor at the U-M Department of Neurology and the first author of the study. “Why does one person in a family get it, and another doesn’t?”

Piecing together a puzzle

In the 1930s, an estimated 50,000 people in the U.S. became lame or otherwise neurologically affected by neurotoxic organophosphates when they drank a contaminated batch of “ginger jake,” an alcohol-containing potion that was legal during Prohibition.

Ginger jake suppliers substituted a lubricating oil for the oil usually used, castor bean oil, when castor bean prices went up. A 2003 article in the New Yorker detailed the sad results, which led bands like the Mississippi Sheiks to write songs about the “ginger jake blues.”

More recently, there have been incidents in Fiji, India and Africa when accidental consumption of oils containing neurotoxic organophosphates (instead of cooking oil) caused death or nerve damage for tens of thousands of people. Although scientists don’t yet know the exact manner in which toxic organophosphate exposure leads to progressive and permanent nerve damage, they have learned that this process involves disturbance of an enzyme, NTE, contained within nerves.

Fink examined members of two families who had progressive weakness and spasticity (tightness) in their legs, as well as muscle atrophy in their hands, shins and feet. James Albers, M.D., Ph.D., a U-M professor of neurology and an expert in neuromuscular disorders, studied nerve and motor function. Rainier performed genetic studies and determined that the gene for the condition was on a region of chromosome 19.

Mark Leppert, Ph.D., co-chair of human genetics at the University of Utah, and his team performed genetic analysis that confirmed this location and excluded other areas in the genome. Among the many genes in this region of chromosome 19, one gene stood out as particularly likely: the gene that encodes for NTE. Because of its known role in organophosphate-induced neurological disease, the NTE gene was considered an important candidate gene and was studied immediately.

Analysis showed that the affected people in each family had NTE gene mutations. These mutations altered a critical part of the NTE protein called the esterase domain. Fink has named the inherited condition “NTE motor neuron disease.” It begins in childhood and progresses slowly, with symptoms of weakness and spasticity in the legs and muscle atrophy in the hands and lower legs.

Next, Fink and his team want to learn if mutations in the NTE gene happen in other types of motor neuron disease such as ALS, and if the mutations make a person more vulnerable to neurological damage from organophosphate exposure. Fink’s lab is currently using fruit flies as a model to study the NTE mutations, with the goal of finding treatments for people with motor neuron disease.

Other authors include Melanie Bui, Erin Mark, Donald Thomas, Debra Tokarz, Lei Ming, Colin Delaney, and James W. Albers, M.D., Ph.D., of the U-M Department of Neurology; Rudy J. Richardson, D.Sc, associate professor of neurology at U-M Medical School and Dow Professor of Toxicology in Environmental Health Sciences at the U-M School of Public Health; and Nori Matsunami, Jeff Stevens, Hilary Coon and Mark Leppert, Ph.D. of the University of Utah.

A patent application for the use of the NTE gene and protein sequence for diagnosis and treatment is pending. The University of Michigan through its Office of Technology Transfer is actively seeking a licensing partner to help bring the technology to market.

Citation: American Journal of Human Genetics, Volume 82, Issue 3, 780-785, 3 March 2008

Funds for this research came from the National Institutes of Health, the Veterans Affairs Merit Review, the U-M Institute of Gerontology, the Spastic Paraplegia Foundation and the National Organization for Rare Disorders

Gene newly linked to inherited ALS may also play role in common dementia

By Michael Purdy

Feb. 20, 2008 -- Scientists at Washington University School of Medicine in St. Louis have linked a mutation in a gene known as TDP-43 to an inherited form of amyotrophic lateral sclerosis (ALS), the neurodegenerative condition often called Lou Gehrig's disease.

Researchers found the connection intriguing because studies by other groups have revealed abnormalities in the TDP-43 protein in both sporadic and inherited ALS, as well as in several other neurodegenerative disorders.

"The potential link to sporadic ALS is particularly interesting. If we can confirm TDP-43's association with inherited ALS, mutating this gene may give us a way to model sporadic ALS in laboratory animals for the first time," says senior author Nigel Cairns, Ph.D., research associate professor of neurology and pathology and immunology. "That could give us a potent tool for better understanding ALS and developing new treatments."

The study appears February 20 in Annals of Neurology. It was conducted at the Hope Center for Neurological Disorders, a partnership between the University and Hope Happens, a St. Louis-based non-profit organization dedicated to raising funds for neurological research.

Approximately 30,000 U.S. citizens have ALS, a condition that kills motor neurons, the nerve cells that control muscles. This causes gradually increasing paralysis and typically leads to death over a course of several years. Approximately five to 10 percent of all ALS cases are inherited; the rest are sporadic.

Hope Happens was founded by Christopher Hobler, a St. Louisan who developed ALS and died from the disorder in 2005. Hobler's grandfather and cousin had previously died from the disorder, and Hobler and his family founded Hope Happens to promote awareness of ALS and other neurodegenerative conditions and to raise money for research to develop new treatments and cures.

In 1993, scientists linked an inherited form of ALS to mutations in the gene for a protein called superoxide dismutase-1 (SOD1). Since then, many had thought altering the SOD1 gene's function was the most promising way to model and understand sporadic ALS.

"That has all been turned upside down in the last two years, though," says Cairns. "In that time, abnormal TDP-43 deposits have been identified in sporadic ALS cases and in some inherited forms of ALS that don't involve a SOD1 mutation."

TDP-43 is an influential regulator of messenger RNA splicing, the process that edits protein-building instructions from DNA to allow the proteins to be built properly. TDP-43 abnormalities in ALS patients have included altered folding and a chemical change known as phosphorylation, both of which can radically alter the protein's function.

As a result, several research groups have been looking for a case where a mutation in the TDP-43 gene was linked to inherited disease. The new study is the first to tentatively establish such a link. Michael Gitcho, Ph.D., a postdoctoral research associate in Dr. Cairns' lab, and colleagues found that every member of a family affected by an inherited form of ALS had a particular mutation in TDP-43. Next, they looked at 1,505 people not related to the family and unaffected by ALS. This second search found no examples of the same mutation.

Because the family they studied is small, scientists need further evidence to confirm that the mutation is causing ALS. Researchers are working to introduce the mutated human TDP-43 gene they identified in the family into a transgenic mouse model. They hope the mouse will generate a model for ALS-like pathology.

If this affirms the link, they will begin tracing the effects of the mutation on genes whose splicing is regulated by TDP-43, working to identify key links in the chain reaction that leads to motor neuron death. These links may become new targets for pharmaceutical treatments.

What they learn may also shed light on other neurodegenerative disorders. Co-author Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry, notes that abnormal TDP-43 has been found in patients with frontotemporal dementia, the second most common cause of early-onset dementia after Alzheimer's disease.

"As our understanding of these diseases progresses, we're starting to see common elements," says Goate. "This protein may allow us to link together a number of important disease entities and pinpoint new targets for therapeutic intervention."

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Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ. TDP-43 A315T mutation in familial motor neuron disease. Annals of Neurology, online edition.

Funding from the National Institutes of Health for the Alzheimer's Disease Research Center, Washington University School of Medicine, the Arizona Alzheimer's Disease Research Consortium, the Hope Center for Neurological Disorders, the Buchanan Fund and the Barnes-Jewish Hospital Foundation supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's Hospitals. The School of Medicine is one of the leading medical research, teaching, and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's Hospitals, the School of Medicine is linked to BJC HealthCare.

Research Suggests New Direction For ALS Treatment

Copyright 2008 Medicalnewstoday.com

A research team from Wake Forest University School of Medicine is the first to show that injections of a protein normally found in human cells can increase lifespan and delay the onset of symptoms in mice with ALS (amyotrophic lateral sclerosis), or Lou Gehrig's disease.

Reporting in the Nov. 28th issue of the Journal of Neuroscience, the researchers said treatments of recombinant heat shock protein 70 (Hsp70) increased total lifespan by 10 percent significantly more than Riluzole®, the only ALS treatment approved by the U.S. Food and Drug Administration. They cautioned that while the research suggests a new treatment approach for ALS, it is not ready for studies in patients.

"This is another piece in the puzzle of what causes ALS and how to best treat it," said David Gifondorwa, lead author and a Ph.D. candidate at Wake Forest. "It's possible that one day a treatment based on this finding could be part of a 'cocktail' for attacking the disease from different fronts."

ALS is a disease that causes death of motor neurons, the nerve cells that control muscles. There are two sets of motor neurons affected in ALS: upper motor neurons that are located in the brain and brainstem, and lower motor neurons that are located in the spinal cord but send out nerve fibers, or "transmission lines," to connect with muscles.

The study focused on the lower motor neurons. Previous research by Wake Forest and others had shown that before the motor neuron dies, it first detaches, or denervates, from the muscle.

"There is a growing amount of research that suggests denervation is what happens first," said Carol Milligan, Ph.D., senior researcher. "Our hope is that the results of our study will help steer thinking into focusing on what happens at the junction of nerve and muscle. It is possible that if we can develop treatments to maintain the contact of nerves and muscle, we can maintain the health of the motor neurons longer."

The current study involved mice that are genetically engineered to develop ALS. They have the same genetic defect found in about 2 to 3 percent of human ALS cases. The mice were treated with either a placebo, Riluzole, or Hsp70, a protein made by the cells of both animals and humans. Heat shock proteins are produced by cells as part of the stress response to protect themselves from injury. In several animal models of ALS, motor neurons do not mount a typical stress response.

The researchers tested whether injecting the mice with Hsp70 would help protect the motor neurons. The mice in the study got injections of Hsp70 three times a week beginning 50 days after birth. The injections were effective at increasing lifespan, delaying symptom onset, preserving motor function and prolonging motor neuron survival. Lifespan increased by 10 days in the Hsp70 treated mice, compared to one day in the Riluzole group. Ten days represents about 10 percent increase in the lifespan of this animal model of ALS. In humans, Riluzole increases lifespan by about 60 days.

The treatment was not detected in the central nervous system, leading the researchers to believe that it acts not in the spinal cord, but where the neurons attach to muscle. Treatment with Hsp70 resulted in an increased number of innervated muscles, compared to the other groups.

"The protein seems to work at the neuromuscular junction," said Gifondorwa. "Because current ALS treatments work at the spinal cord, our finding suggests the possibility of a cocktail that works to prevent damage in both locations may prove more beneficial."

Wake Forest is currently studying new ALS treatments, as well as working to better understand what goes wrong to cause the disease. The Wake Forest ALS Center, under the directorship of James Caress, M.D., will soon be part of the clinical trial of Arimoclomol, a drug that works to enhance the stress response of nerve cells. And, a team of nine researchers from five departments that includes Milligan and Caress is developing a series of projects with the goal of understanding more about the early events in the development of ALS.

In mice, the researchers will study changes that occur in the muscles, nerves and spinal cord with denervation. They will also work to determine which nerves and muscles are affected first. In humans with ALS, they hope to look at early muscle changes using advanced imaging technology.

Co-researchers on the current study were Mac Robinson, Ph.D., Crystal Hayes, M.S., Anna Taylor, Ph.D., David Prevette, B.S., Ronald Oppenheim, Ph.D., and James Caress, M.D.

Targeting Astrocytes Slows Disease Progression In Lou Gehrig's Disease, Study Shows

ScienceDaily (Feb. 4, 2008) — In what the researchers say could be promising news in the quest to find a therapy to slow the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, scientists at the University of California, San Diego (UCSD) School of Medicine have shown that targeting neuronal support cells called astrocytes sharply slows disease progression in mice.

The study, conducted in the laboratory of Don Cleveland, Ph.D., UCSD Professor of Medicine, Neurosciences and Cellular and Molecular Medicine and member of the Ludwig Institute for Cancer Research, will appear in the advance online publication on Nature Neuroscience's website on February 3rd.

"Mutant genes that cause ALS are expressed widely, not just in the motor neurons," Cleveland explained. "Targeting the partner cells like astrocytes, which live in a synergistic environment with the neuron cells, helps stop the 'cascade of damage.' Therapeutically, this is the big news."

ALS is a progressive disease that attacks the motor neurons, long and complex nerve cells that reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body, which act to control voluntary movement. Degeneration of the motor neurons in ALS leads to progressive loss of muscle control, paralysis and untimely death. Estimated to affect some 30,000 Americans, most people are diagnosed with ALS between the ages of 45 and 65. Typically, ALS patients live only one to five years after initial diagnosis.

In findings published in Science in June 2006, Cleveland and his colleagues showed that in early stages of inherited ALS, small immune cells called microglia are damaged by mutations in the SOD1 protein, and that these immune cells then act to significantly accelerate the degeneration of the motor neurons. The new study demonstrates that much the same thing happens to astrocytes, support cells that are essential to neuronal function, and whose dysfunction is implicated in many diseases. The researchers speculate that the non-neuronal cells play a vital role in nourishing the motor neurons and in scavenging toxins from the cellular environment. As with microglia, the helper role of astrocytes is altered due to mutations in the SOD1 protein.

"We tested what would happen if we removed the mutant gene from astrocytes in mouse models," said Cleveland. "What happened was it doubled the lifespan of the mouse after the onset of ALS."

Astrocytes are key components in balancing the neurotransmitter signals that neurons use to communicate. To examine whether mutant SOD1 damage to the astrocytes contributes to disease progression in ALS, researchers in the Cleveland lab used a genetic trick to excise the mutant SOD1 gene, but only in astrocytes. Reduction of the disease-causing mutant SOD1 in astrocytes did not slow disease onset or early disease; however, the late stage of the disease was extended, nearly doubling the normal life expectancy of a mouse with ALS.

"Silencing the mutant gene in the astrocytes not only helps protect the motor neuron, but delays activation of mutant microglia that act to accelerate the progression of ALS," said Cleveland.

The findings show that mutant astrocytes are likely to be viable targets to slow the rate of disease spread and extend the life of patients with ALS. Cleveland added that this may prove especially important news to researchers in California and elsewhere working with stem cells. "This gives scientists a good idea of what cells should be replaced using stem cell therapy. Astrocytes are very likely much easier to replace than the slow-growing motor neuron."

Additional contributors to the study include Koji Yamanaka, Seung Joo Chun and Severine Boillee, Ludwig Institute for Cancer Research and UCSD Department of Medicine and Neuroscience; Noriko Fujimore-Tonou and Hirofumi Yamashita, Yamanaka Research Unit, RIKEN Brain Science Institute, Saitama, Japan; David H. Gutmann, Department of Neurology, Washington University, St. Louis; Ryosuke Takahashi, Department of Neurology, Kyoto University, Japan; and Hidemi Misawa, Department of Pharmacology, Kyoritsu University of Pharmacy, Tokyo.

The work was supposed by grants from the National Institutes of Health, the Packard ALS Center at Johns Hopkins University, the Muscular Dystrophy Association, the Uehara Memorial Foundation, the Nakabayashi Trust for ALS Research, and the Ministry of Education, Culture, Sports Science and Technology of Japan.

Lithium slows ALS progression

Copyright 2008 News-Medical.net

Daily doses of lithium, a drug used to treat bipolar disorder, have been found to delay progression of amyotrophic lateral sclerosis (ALS) in an Italian study of 44 people with the disease.

No other treatment to date has shown such a dramatic effect on this paralyzing and fatal disease of adults, which affects some 30,000 Americans.

Francesco Fornai at the University of Pisa (Italy), with colleagues at the University of Novara (Italy) and the Santa Lucia Foundation in Rome, announced their results online today in Proceedings of the National Academy of Sciences.

At the end of a 15-month trial that began in October 2005, about 30 percent of the patients that took riluzole, a drug known to have modest benefit in ALS, had died, while all those receiving riluzole plus lithium had survived. The disease progressed markedly in the riluzole-only group but progressed very slowly in the riluzole-plus-lithium group.

"Although the number of study participants is small, the results are very intriguing," said Dr. Valerie Cwik, MDA medical director and vice president of Research. "MDA has already had conversations with researchers in the United States to follow up on these results with a larger, confirmatory study."

Sixteen trial participants were randomly selected to receive 50 milligrams a day of riluzole plus two daily doses of 150 milligrams of lithium carbonate. (If necessary, doses were adjusted up to 450 milligrams a day during the study to maintain targeted blood levels.)

The remaining 28 participants were randomly assigned to receive riluzole only.

The two groups were carefully matched with respect to the number of patients with bulbar ALS, the most rapidly progressive form, and pulmonary function.

A parallel study in mice with a genetic form of ALS suggested that lithium works by increasing autophagy, a process in which worn-out or abnormal cellular components are destroyed, and boosting the number of mitochondria, the energy-producing units of cells.

Lithium must be taken under a doctor's supervision and with frequent monitoring of blood levels. Early signs of lithium toxicity include diarrhea, vomiting, drowsiness, weakness and lack of coordination. Later signs include giddiness, blurred vision, ringing in the ears and a large output of dilute urine.

U of I study finds drug prolongs life of mice with ALS

By TONY LEYS • REGISTER STAFF WRITER • January 25, 2008

University of Iowa researchers say they've found a drug that doubles the life span of mice suffering from a form of Lou Gehrig's disease.

The scientists caution that the drug has been tried only on animals with a relatively rare, inherited version of the disease, and they're not sure it would help humans. On the other hand, they say the discovery could be a major step toward a treatment for people afflicted with the condition.

Lou Gehrig's, also known as amyotrophic lateral sclerosis, is a degenerative, fatal nerve disease that strikes 5,600 Americans per year. It causes them to lose muscle control, eventually leaving them unable to breathe.

The U of I researchers make up one of numerous teams investigating the disease's causes and proposing treatments.

Biology professor John Engelhardt, who helped lead the study, said the drug is a purified form of apocynin, a plant extract that is used in some nutritional supplements. He said the team hopes to start testing the drug for safety in humans within three years, and to study whether it also might help people who have the more common, "sporadic" form of the disease.

Engelhardt said the experiments indicate the drug slows the disease's progress, but doesn't reverse it.

"There is a very significant correlation between how early you get on the drug and how long you live - if you're a mouse," he said. If the results translate to humans, people would have an incentive to be tested early, so they could start taking the drug before symptoms appear.

The U of I study looks only at mice with an inherited form of the disease, which accounts for about 2 percent of human cases. The researchers reported last fall that they managed to double the life span of such mice by manipulating their genes. Such genetic treatment is complicated and could be dangerous, and the scientists did not believe it would be practical in humans.

In the new study, the researchers say they've managed to produce the same results by using a drug to dampen the influence of the problem gene. The experiment showed that mice that drank water laced with the drug lived about 250 days, twice as long as untreated mice.

The study was published Thursday in the Journal of Clinical Investigation. The 12-page paper is complicated, even as these sorts of things go. But the gist of it is that the drug helps control production of "reactive oxygen species," such as hydrogen peroxide, in cells of mice bred to have the disease. The molecules are naturally occurring substances that are necessary for life, but they can be toxic in large quantities. Researchers believe that people with certain inherited forms of Lou Gehrig's disease produce too many of the molecules, which can lead to inflammation and death of nerve cells.

A national expert who expressed caution about the U of I's earlier study called the new results "very promising."

Dr. Lucie Bruijn, science director of the ALS Association, said the study appears to break new ground.

"I'm extremely enthusiastic," she said. "I think the group is teasing out a new and interesting pathway."

However, Bruijn warned that ALS patients should not rush out and buy dietary supplements with apocynin.

"They would be crazy to do that," she said. "I would be very cautious."

She acknowledged that many ALS patients are desperate because they have few good options to fight the fatal disease. But she said tests could show that apocynin causes dangerous side effects, including eye damage.

Bruijn said she hopes to see other teams replicate the U of I study. She also said it's unclear whether the drug would help people who have the more common form of the disease. The main obstacle to answering that question, Bruijn said, is scientists have been unable to develop mice with the common form of ALS.

Scientists Discover Why Animal Studies May Lead to Ineffective ALS Drugs

Study Recommends Guidelines for Using Leading Mouse Model of ALS

CAMBRIDGE, Mass., Jan. 22 /PRNewswire/ -- A five-year study of more than 70 drugs, many with reported survival benefit in a mouse model of the inherited form of amyotrophic lateral sclerosis -- ALS or Lou Gehrig's Disease, concluded the apparent positive effects were largely due to previously unrecognized variables in the study design, scientists reported today. The study included the drug riluzole, the only drug approved by the U.S. Food and Drug Administration for ALS treatment.

The study was undertaken to evaluate possible ALS treatments, and to put money and resources behind the most promising ones. Despite the findings, the investigators said the study establishes guidelines for evaluating preclinical mouse studies in ALS, and provides a starting point for standardizing the use of this animal model of ALS.

"Researchers have been puzzled as to why animal results have failed to replicate in the clinic," said Sean A. Scott, the principal investigator and president of the Cambridge-based ALS Therapy Development Institute, which conducted the study. "It appears this animal model is subject to greater variability than many investigators realized. The exciting part of this study is that one can now identify and substantially eliminate the biological variability to fully exploit the value of this animal model for identifying effective treatments."

Scientists screened the drugs in 18,000 genetically engineered mice, across 221 independent studies, only to find no significantly positive outcomes for any of the compounds previously thought to extend the lifespan of the ALS mouse commonly used in preclinical studies. The study was published in Internet edition of the journal, Amyotrophic Lateral Sclerosis.

"We expected to replicate previous reports of efficacy and to establish both positive controls and metrics to gauge future therapeutic potential," added Scott. "While we were able to measure a significant difference in survival between males and females, we observed no significant positive or negative effects for any of the 70-plus compounds tested, including several previously reported as efficacious."

According to Sharon Hesterlee, Ph.D., vice president, translational research for the Muscular Dystrophy Association, the Institute's capacity to conduct industrial-scale research laid the groundwork for the MDA's decision to form a three-year, $36 million research collaboration with it last year. "This important study highlights the need to better understand and to standardize the field's use of this mouse model of ALS, particularly when it's used as the basis for launching a human clinical trial."

Through sophisticated computer modeling and data mining, the researchers were able to determine that the discrepancies in previous studies were largely caused by biological and genetic differences, including animal gender. Unless the studies were tightly controlled, noise in the experimental system would swamp most signals and could be interpreted as a positive result.

The research failed to replicate several studies in the SOD1 mouse model that have led to clinical trials of drugs that showed promise for treating ALS. Their results showed the compounds minocycline, creatine, ritonavir, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI-P131, thalidomide, and riluzole had no survival benefit at their reported routes and doses. The therapeutic effect of the FDA-approved drug riluzole is known to be marginal, providing on average only two months extended survival in ALS patients.

"When we put these results in the context of the millions of dollars spent on ALS research, one can appreciate the huge economic impact a study of this kind can have," said Augie Nieto, chairman of the ALS Therapy Development Institute. "This study shows how rigorous research can be accomplished through the power of a nonprofit mission that brings together patients, doctors and researchers toward finding a cure for ALS and other neuromuscular diseases." Nieto and his wife serve as co-chairpersons of MDA's ALS Division. Nieto received a diagnosis of ALS in March 2005.

About ALS

ALS is a chronic, progressive neurodegenerative disease that leads to paralysis due to the death of motor neurons in the spinal cord and brain. Patients become trapped within their bodies, unable to speak, eat, or breathe on their own. Most succumb to respiratory failure within three to five years of diagnosis. A small percentage of ALS in humans is caused by a mutation in the gene coding for the SOD1 protein, an enzyme that helps prevent oxygen toxicity in cells. It's not known what ultimately causes sporadic ALS, which constitutes some 95% of all disease cases.

ALS strikes 2:100,000 Americans per year, typically in middle or old age, with a slight preference for males. There are approximately 30,000 diagnosed patients in the United States, with a similar number in Europe. Approximately 90% of cases are sporadic and 5% to 10% are familial. About 20% of ALS patients live 5 years or more, 10% survive more than 10 years, and 5% live 20 years after diagnosis. Quality of life becomes a huge challenge for patients. In later stages of the disease, patients are alert mentally but functionally quadriplegic in many cases, aware of impending death. The cost of care at later stages reaches an average of $200,000 per year.

About ALS Therapy Development Institute

The ALS Therapy Development Institute (http://www.als.net), based in Cambridge, Mass., operates the world's largest research and development program focused exclusively on ALS. Its staff of 30 scientists and research technicians work on behalf of ALS patients to discover and advance novel therapeutics for treating and ultimately curing ALS. The non-profit biotechnology institute excels in identifying novel disease targets, discovering compounds that may act against these targets, and screening potential treatments for clinical development.

Stems of Hope for Treating Incurable Diseases

Two Professors at the Hadassah University Hospital in Jerusalem have succeeded in improving the condition of MS and ALS patients by using stem cells transplants. The researchers extracted stem cells from each patient's bone marrow, cultured them, and then injected them into the patients' spine. The encouraging results of this small clinical study may give hope to those who suffer from these incurable diseases, as well as to researchers developing stem cells techniques for treatment of other diseases.

Multiple Sclerosis (MS) and Amytrophic Lateral Sclerosis (ALS) are diseases related to the nervous system that currently do not have a cure. MS is the most common neurodegenerative disease. It is a chronic autoimmune inflammatory disease in which an individual’s immune system attacks the central nervous system (CNS), gradually destroying the myelin layers that surround and electrically insulate specific parts of neurons (nerve cells). The myelin layers are important because they enable neural impulses to propagate along the neurons at a high speed. Although the CNS is able to recruit stem cells of remyelinating cells (named oligodendrocytes), these cells are somehow inhibited in repeatedly attacked areas. For this reason, repeated attacks of the immune system can lead to severe impairment of the neural signals and to scarring of the damaged portion of the neuron. MS symptoms depend on the location of the multiple lesions’ occurrence in the CNS. These neurological deficits are progressively accumulated, leading to functional sphincter, sensor, and motor deficiencies. The patient's vision and balance are also damaged.

Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig's Disease) is one of the most common neuromuscular diseases worldwide. It is a progressive, usually fatal, neurodegenerative disease caused by the degeneration of motor neurons, the nerve cells in the CNS that control voluntary muscle movement. As motor neurons degenerate and die, neural signaling to the muscles ceases, resulting in muscle weakness, atrophy, and twitches throughout the body. Patients may ultimately lose their ability to control all voluntary movements except of the eyes. The cause of ALS is not known, and no cure has been found for the disease.

Mesenchymal stem cells are found in the bone marrow and are multipotent - they can differentiate into a variety of cell types, including CNS cells (such as oligodendrocyte-like cells), if cultured in the right conditions. They have also been shown to be able to migrate into the brain. These features make autologous (self) bone marrow transplants, on which the treatment developed at Hadassah University Hospital was based, a possible method for treating various neural diseases.

Professor Dmitrius Karussis, a Senior Neurologist at Hadassah and the Director of the new Multiple Sclerosis Center, worked in collaboration with the University of Athens, and with Professor Shimon Slavin, the Former Director of the Department of Bone Marrow Transplantation (BMT) and the BMT Laboratory at Hadassah. The scientists successfully isolated mesenchymal stem cells from the patients' bone marrow, cultured them under special conditions, and generated over 50 million stem cells within two months. The mesenchymal cells were marked so that the scientists could track them and verify that they reach the intended destination in the patient's body. The cells were then transplanted by a lumbar injection into the patient's spinal cord (into the spinal fluid of the CNS). Each patient served as his/her own bone marrow donor.

According to Professor Karussis, the effectiveness of stem cells was initially studied in laboratory animals, where it was found that stem cells from bone marrow can reduce cerebral damage and improve the animal's functioning. During the past two years Professor Karussis has conducted clinical trials with 9 patients suffering from multiple sclerosis and with 16 patients suffering from ALS. "Most of the patients who underwent this process report an improvement in their condition," Professor Karussis said. The purpose of this initial trial was to identify undesired effects of the procedure. So far, no major safety issues have been encountered. However, a controlled larger scale clinical trial should be conducted in order to establish the safety and efficacy of the treatment.

Even more hope for MS - using
virtual reality to improve walking

Directed to differentiate into specific cell types, stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a variety of diseases. A number of stem cell therapies already exist, particularly bone marrow transplants that are used to treat leukemia. Medical researchers expect stem cell technologies to treat a wider variety of diseases in the future, including cancer, Parkinson's and Alzheimer's diseases, spinal cord injuries, strokes, heart disease, diabetes and arthritis. The clinical trial in Hadassa is supporting this approach, giving patients suffering from various diseases a hope for effective treatments or even cures.

Mutation in one gene tied to Lou Gehrig's disease

Promising Lou Gehrig’s disease drug fails trial

CHICAGO (Reuters) - A mutation in a single gene may raise one's risk of getting amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, by as much as 30 percent, offering a potential new target for drug research, Dutch scientists said on Sunday.

They said a variant in the DPP6 gene may give rise to ALS in people without a family susceptibility to the untreatable and fatal disease.

Familial ALS, which accounts for 10 percent of all cases of the disease, has been linked with mutations in a number of other genes. Researchers have had less luck finding a gene associated with non-familial, sporadic ALS, which accounts for 90 percent of ALS cases.

But researchers at the University Medical Center Utrecht said a SNP or single-letter change in the genetic code of the DPP6 gene is "consistently and strongly associated with susceptibility to amyotrophic lateral sclerosis in different populations of European ancestry."

The DPP6 gene controls an enzyme found mostly in the brain that has been linked with spinal cord injury in rats.

Leonard van den Berg and a team of researchers used a new approach called a genome-wide association study to comb through the genetic code of 1,700 individuals with the disease, and compared that to the genome of more than 1,900 healthy people.

The samples came from three European populations and recently reported data from ALS patients in the United States.

What they discovered was a single variant in DPP6 that was associated with ALS in each population. This variant increased the risk of getting the disease by about 30 percent.

The researchers said this is the first genetic risk factor found consistently across many populations.

"Identification of a common variant within DPP6 is an exciting first step in the genetic study of sporadic ALS, and it opens up new avenues for studying the molecular basis of this devastating disease," van den Berg and colleagues wrote in the journal Nature Genetics.

ALS progressively kills nerve cells that control muscle movements known as motor neurons in the brain and spinal cord. It is sometimes called Lou Gehrig's disease for taking the life of the famous New York Yankees baseball player in 1941.

About 5,600 people in the United States are diagnosed with ALS each year, according to the ALS Association.

Stress protein helps delay ALS in mice: study

CHICAGO (Reuters) - A human protein generated while the body encounters environmental stress helped delay symptoms of amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease in mice, U.S. researchers said on Tuesday.

Genetically engineered mice with ALS that were injected with this protective protein lived 10 percent longer than untreated mice.

"When we administered the protein every other day, we saw mice develop symptoms later than untreated mice. They performed better on a behavior test and they lived longer," said Carol Milligan, a researcher at Wake Forest University School of Medicine, whose study appears in the Journal of Neuroscience.

ALS progressively kills nerve cells that control muscle movements known as motor neurons.

Milligan, in a telephone interview, said the protein -- known as recombinant heat shock protein 70 -- appears to slow the death of motor neurons near the muscle.

Before a neuron dies, it typically detaches from the muscle, a process called denervation. Milligan said she believes the protein helped delay this process in the ALS mice.

Other studies of ALS in animals have shown the motor neurons do not behave normally when exposed to stress.

Milligan and Wake Forest