Posts tagged motor neurons

Studies of a therapy designed to treat amyotrophic lateral sclerosis (ALS) suggest that the treatment dramatically slows onset and progression of the deadly disease, one of the most common neuromuscular disorders in the world. The researchers, led by teams from The Research Institute at Nationwide Children’s Hospital and the Ludwig Institute at the University of California, San Diego, found a survival increase of up to 39 percent in animal models with a one-time treatment, a crucial step toward moving the therapy into human clinical trials.

The therapy reduces expression of a gene called SOD1, which in some cases of familial ALS has a mutation that weakens and kills nerve cells called motor neurons that control muscle movement. While many drug studies involve only one type of animal model, this effort included analysis in two different models treated before and after disease onset. The in-depth study could vault the drug into human clinical trials, said Brian Kaspar, PhD, a principal investigator in the Center for Gene Therapy at Nationwide Children’s and a senior author on the research, which was published online Sept. 6 in Molecular Therapy.

“We designed these rigorous studies using two different models of the disease with the experimenters blinded to the treatment and in two separate laboratories,” said Dr. Kaspar, who collaborated on the study with a team led by Don Cleveland, PhD, at the University of California, San Diego. “We were very pleased with the results, and found that the delivery approach was successful in a larger species, enabling us to initiate a clinical translational plan for this horrible disease.”

There currently is no cure for ALS, also called Lou Gehrig’s disease. The Centers for Disease Control and Prevention estimates there are about 5,000 new cases in the U.S. each year, mostly in people age 50 to 60. Although the exact cause of ALS is unknown, more than 170 mutations in the SOD1 gene have been found in many patients with familial ALS, which accounts for about 2 percent of all cases.

SOD1 provides instructions for making an enzyme called superoxide dismutase, which is found throughout the body and breaks down toxic molecules that can be damaging to cells. When mutated, the SOD1 gene yields a faulty version of the enzyme that is especially harmful to motor neurons. One of the mutations, which is found in about half of all familial ALS patients, is particularly devastating, with death usually coming within 18 months of diagnosis. SOD1 has also been implicated in other types of ALS, called sporadic ALS, which means the therapy could prove beneficial for larger numbers of patients suffering with this disease.

Earlier work by Dr. Kaspar and others found that they could halt production of the mutated enzyme by blocking SOD1 expression, which in turn, they suspected, would slow ALS progression. To test this hypothesis, the researchers would not only need to come up with an approach that would block the gene, but also figure out how to specifically target cells implicated in the disease, which include motor neurons and glial cells. What’s more, the therapy would preferably be administered noninvasively instead of direct delivery via burr holes drilled into the skull.

Dr. Kaspar’s team accomplished the second part of this challenge in 2009, when they discovered that adeno-associated virus serotype 9 (AAV9) could cross the blood-brain barrier, making it an ideal transport system for delivering genes and RNA interference strategies designed to treat disease.

In this new work, funded by the National Institutes of Health, the researchers blocked human SOD1, using a technology known as short hairpin RNA, or shRNA. These single strands of RNA are designed in the lab to seek out specific sequences found in the human SOD1 gene, latch onto them and block gene expression.

In one of the mouse models used in the study, ALS develops earlier and advances more quickly. In the other, the disease develops later and progresses more slowly. All of the mice received a single injection of AAV9-SOD1-shRNA before or after disease onset.

Results showed that in the rapid-disease-progressing model, mice treated before disease onset saw a  39 percent increase in survival compared to control treated mice. Strikingly, in mice treated at 21 days of age, disease progression was slowed by 66 percent. Perhaps more surprising was the finding that even after symptoms surfaced in these models, treatment still resulted in a 23 percent increase in survival  and a 36 percent reduction in disease progression. In the slower-disease-onset model, treatment extended survival by 22 percent and delayed disease progression by 38 percent.

“The extension of survival is fantastic, and the fact that we delayed disease progression in both models when treated at disease onset is what drives our excitement to advance this work to human clinical trials,” said Kevin Foust, PhD, co-first author on the manuscript and an assistant professor in neurosciences at The Ohio State University College of Medicine.

In addition to the potential therapeutic benefit, the study also offers some interesting insights into the biological underpinnings of ALS. The role of motor neurons in ALS has been well documented, but this study also highlighted another key player—astrocytes, the most abundant cell type in the human brain and supporters of neuronal function.

“Recent work from our collaborator Dr. Cleveland has demonstrated that astrocytes and other types of glia are as important if not more important in ALS, as they really drive disease progression,” said Dr. Kaspar. “Indeed, in looking at data from mice, more than 50 percent of astrocytes were targeted throughout the spinal cord by this gene-delivery approach.”

Ideally, a therapy would hit motor neurons and astrocytes equally hard. The best way to do that is to deliver the drug directly into the cerebrospinal fluid (CSF), which would reduce the amount of SOD1 suppression in cells outside the brain and reduce immune system exposure to AAV9—elements that would add weight to an argument for studying the drug in humans.

Injections directly into CSF cannot be done easily in mice, so the team took the study a crucial step further by injecting AAV9-SOD1-shRNA into the CSF of healthy nonhuman primates. The results were just as the team hoped—the amount of gene expression dropped by as much as 90 percent in motor neurons and nearly 70 percent in astrocytes and no side effects were reported, laying the groundwork towards moving to human clinical trials.

“We have a vast amount of work to do to move this toward a clinical trial, but we’re encouraged by the results to date and our team at Nationwide Children’s and our outstanding collaborators are fully committed to making a difference in this disease,” Dr. Kaspar said.

The findings could impact other studies underway in Dr. Kaspar’s lab, including research on Spinal Muscular Atrophy, an often fatal genetic disease in infants and children that can cause profoundly weakened muscles in the arms and legs and respiratory failure.

“This research provides further proof of targeting motor neurons and glial cells throughout the entire spinal cord for treatment of Spinal Muscular Atrophy and other degenerative diseases of the brain and spinal cord, through a less invasive manner than direct injections,” said Dr. Kaspar, who also is an associate professor of pediatrics and neurosciences at The Ohio State University College of Medicine.

(Source: nationwidechildrens.org)

A small group of elusive neurons in the brain’s cortex play a big role in ALS (amyotrophic lateral sclerosis), a swift and fatal neurodegenerative disease that paralyzes its victims. But the neurons have always been difficult to study because there are so few of them and they look so similar to other neurons in the cortex.

In a new preclinical study, a Northwestern Medicine® scientist has isolated the motor neurons in the brain that die in ALS and, for the first time, dressed them in a green fluorescent jacket. Now they’re impossible to miss and easy to study.

The cells slide on neon jackets when they are born and continue to wear them as they age and become sick. As a result, scientists will now be able to track what goes wrong in these cells to cause their deaths and be able to search for effective treatments.

"We have developed the tool to investigate what makes these cells become vulnerable and sick," said Hande Ozdinler, senior author of the study and assistant professor of neurology at Northwestern University Feinberg School of Medicine. "This was not possible before."

Ozdinler and colleagues also identified the motor neurons that don’t die, enabling scientists to study what protects them.

The study will be published in the Journal of Neuroscience on May 1.

ALS, also known as Lou Gehrig’s disease, causes the death of muscle-controlling nerve cells in the brain and spinal cord (motor neurons). It results in rapidly progressing paralysis and death usually within three to five years of the onset of symptoms.

There are about 75,000 upper motor neurons affected in ALS out of some 2 billion cells in the brain. Previously, the only way to study the upper motor neurons was to extract them through surgery, a difficult process that was beyond the scope of most scientists and still didn’t allow examination of the ailing neurons at various stages of the disease.

"You couldn’t study them at the cellular level, so the research field ignored them," Ozdinler said. She is one of the few scientists in the country who studies cortical motor neurons. Most of ALS research has focused on the death of motor neurons in the spinal cord.

Key puzzle piece: Why ALS moves so swiftly

But the brain’s motor neurons are a key piece of the ALS puzzle. Their disintegration explains why the disease advances more swiftly than other neurodegenerative diseases. It had previously been thought that the spinal motor neurons died first and their demise led to the secondary death of the brain’s motor neurons. But Ozdinler’s recent research showed that the motor neurons in the brain and spinal cord die simultaneously.

"The whole system collapses at once," Ozdinler said. "It’s degeneration from both ends which is why the disease moves so swiftly."

Every voluntary movement is initiated and modulated by upper motor neurons — answering a cell phone, typing an email, walking to the store. The upper motor neurons tell the spinal motor neurons what to do. In ALS, both the directing neurons and the neurons that create the movement disintegrate at the same time.

Finding the light that never goes out

Ozdinler spent the last four years figuring out how to permanently sheath cortical motor neurons in fluorescence.

Although scientists can flag spinal cord motor neurons in fluorescence, it wears off as the neuron ages because the process uses an embryonic gene. Ozdinler wanted a longer lasting effect so scientists could study the neuron as it ages and develops ALS. She sorted through 6,000 upper motor neuron genes that are vulnerable to ALS before she found one — UCHL1 — that is expressed through adulthood.

She used that gene — which had been cloned with the fluorescence molecule — and created a mouse model whose upper motor neurons shimmer in green. Then she mated that mouse with an ALS transgenic mouse model. The result is a mouse with fluorescent diseased motor neurons in the brain.

"Now we have a model of one motor neuron population that dies and one that is resistant," Ozdinler said. "That’s the perfect experiment. You can ask what does this neuron have that makes it resistant and what does the other one have that makes it vulnerable? That’s what we will find out."

Marina Yasvoina, a graduate student, and Baris Genc, a postdoctoral fellow, both in Ozdinler’s lab, are the lead authors of the paper. Ozdinler collaborated with Gordon Shepherd, associate professor of physiology, and C.J. Heckman, professor in physiology, both at Feinberg.

"This work was possible thanks to the collaborative nature of Northwestern," Ozdinler said.

(Source: eurekalert.org)

Using a new, stem cell-based, drug-screening technology that could reinvent and greatly reduce the cost of developing pharmaceuticals, researchers at the Harvard Stem Cell Institute (HSCI) have found a compound that is more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) than are two drugs that failed in human clinical trials after large sums were invested in them.

The new screening technique developed by Lee Rubin, a member of HSCI’s executive committee and a professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), had predicted that the two drugs that eventually failed in the third and final stage of human testing would do just that.

“It’s a deep, dark secret of drug discovery that very few drugs have been tested on human-diseased cells before being tested in a live person,” said Rubin, who heads HSCI’s program in translational medicine. “We were interested in the notion that we can use stem cells to correct that situation.”

Rubin’s model is built on an earlier proof of concept developed by HSCI principal faculty member Kevin Eggan, who demonstrated that it was possible to move a neuron-based disease into a laboratory dish using stem cells carrying the genes of patients with the disease.

In a paper published today in the journal Cell Stem Cell, Rubin laid out how he and his colleagues applied their new method of stem cell-based drug discovery to ALS, also known as Lou Gehrig’s disease. The illness is associated with the progressive death of motor neurons, which pass information between the brain and the muscles. As cells die, people with ALS experience weakness in their limbs, followed by rapid paralysis and respiratory failure. The disease typically strikes later in life. Ten percent of cases are genetically predisposed, but for most patients there is no known trigger.

Rubin’s lab began by studying the disease in mice, growing billions of motor neurons from mouse embryonic stem cells, half normal and half with a genetic mutation known to cause ALS. Investigators starved the cells of nutrients and then screened 5,000 druglike molecules to find any that would keep the motor neurons alive.

Several hits were identified, but the molecule that best prolonged the life of both normal and ALS motor neurons was kenpaullone, previously known for blocking the action of an enzyme (GSK-3) that switches on and off several cellular processes, including cell growth and death. “Shockingly, this molecule keeps cells alive better than the standard culture medium that everybody keeps motor neurons in,” Rubin said.

Kenpaullone proved effective in several follow-up experiments that put mouse motor neurons in situations of certain death. Neuron survival increased in the presence of the molecule whether the cells were programmed to die or were placed in a toxic environment.

After further investigation, Rubin’s lab discovered that kenpaullone’s potency came from its ability also to inhibit HGK, an enzyme that sets off a chain of reactions that leads to motor neuron death. This enzyme was not previously known to be important in motor neurons or associated with ALS, marking the discovery of a new drug target for the disease.

“I think that stem cell screens will discover new compounds that have never been discovered before by other methods,” Rubin said. “I’m excited to think that someday one of them might actually be good enough to go into the clinic.”

To find out if kenpaullone worked in diseased human cells, Rubin’s lab exposed patient motor neurons and motor neurons grown from human embryonic stem cells to the molecule, as well as two drugs that did well in mice but failed in phase III human clinical trials for ALS. Once again, kenpaullone increased the rate of neuron survival, while one drug saw little response, and the other drug failed to keep any cells alive.

According to Rubin, before kenpaullone could be used as a drug, it would need a substantial molecular makeover to make it better able to target cells and find its way into the spinal cord so it can access motor neurons.

“This is kind of a proof of principle on the do-ability of the whole thing,” he said. “I think it’s possible to use this method to discover new drug targets and to prevalidate compounds on real human disease cells before putting them in the clinic.”

Rubin’s next steps will be to continue searching for better druglike compounds that can inhibit HGK and thus enhance motor neuron survival. He believes that the new information that comes out of this research will be useful to academia and the pharmaceutical industry.

“These kinds of exploratory screens are hard to fund, so being part of the HSCI” — which provided some of the funding — “has been absolutely essential,” Rubin said.

(Source: news.harvard.edu)

The initial clinical trial of a novel approach to treating amyotrophic lateral sclerosis (ALS) – blocking production of a mutant protein that causes an inherited form of the progressive neurodegenerative disease – may be a first step towards a new era in the treatment of such disorders. Investigators from Massachusetts General Hospital (MGH) and Washington University School of Medicine report that infusion of an antisense oligonucleotide against SOD1, the first gene to be associated with familial ALS, had no serious adverse effects and the drug was successfully distributed thoughout the central nervous system.

"This therapy directly targets the cause of this form of ALS – a mutation in SOD1, which was originally discovered here at the MGH by my mentor Robert Brown," says Merit Cudkowicz, MD, chief of Neurology at MGH and senior author of the report in Lancet Neurology, which has been released online. “It’s very exciting that we have reached a stage when we can start clinical trials against this type of ALS.”

ALS causes the death of motor neurons in the brain and spinal cord, stopping transmission of neural signals to nerve fibers and leading to weakness, paralysis and usually death from respiratory failure. Only 10 percent of ALS cases are inherited, and mutations in SOD1 – which produce an aberrant, toxic form of the protein – account for about 20 percent of familial cases. Although that first SOD1 mutation was identified 20 years ago by the team lead by Brown – who is now professor and chief of Neurology at the University of Massachusetts Medical School – a technology that directly addresses such mutations became available only recently.

The current study, the first author of which is Timothy Miller, MD, PhD, of Washington University, used what are called antisense oligonucleotides – small, single-stranded DNA or RNA molecules that prevent production of a protein by binding to its messenger RNA. While antisense medications have been tested against several types of disease, this was the first trial in a neurological disorder, making the assurance of safety – a primary goal of a phase 1 study – particular important. Studies in animal models led by Miller and others found that the experimental antisense drug used in this trial reduced expression of mutated and nonmutated SOD1 and slowed the progression of ALS.

Conducted at the MGH, Washington University, Johns Hopkins University and the Methodist Neurological Institute in Houston, the trial enrolled a total of 21 patients with SOD1 familial ALS. Four sequential groups of participants received spinal infusions over an 11-hour period of the antisense drug or a placebo, with the active drug being administered at one of four dosage levels. Since participants in one group were free to join a subsequent group more than 60 days later, seven received two infusions and two received a total of three.

Some of the participants reported the type of adverse effects typically associated with spinal infusions – headache and back pain – with no difference between the active drug and placebo groups. Participants who receive subsequent infusions reported fewer adverse effects. Cerebrospinal fluid samples taken immediately after infusion revealed the presence of the antisense oligonucleotidein all participants receiving  the drug at levels close to what was predicted based on animal studies. Analysis of spinal cord samples from one participant who had later died from ALS found drug levels highest at the site of the infusion and lowest at the furthest point and suggested that prior estimates of how long the drug would persist in the spinal cord were accurate.

Cudkowicz notes that the next step will be a larger study to address long-term safety and take a first look at the effectiveness of antisense treatment against ALS “This is a very important step forward for neurodegenerative disorders in general,” she explains. “There are other ALS gene mutations that antisense technology may be useful against. There also is an ongoing study of a different oligonucleotide against spinal muscular atrophy, and ongoing preclinical studies in Huntington’s disease, myotonic dystrophy and other neurological disorders are in development.

"The first person with ALS that I cared for had SOD1 ALS," she adds, "and I promised her a commitment to finding a treatment for this form of the disease. It’s so gratifying to finally be at the stage of knowledge where we can start testing this treatment in patients with SOD1 ALS. We also hope that this treatment may apply to the broader population of patient with sporadic ALS." Cudkowicz is the Julieanne Dorn Professor of Neurology at Harvard Medical School. 

(Source: massgeneral.org)

Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease’s progress.

In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes — cells that create insulation for the nerves of the central nervous system — long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons — cells that govern movement — died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.

The researchers also found, to their surprise, that suppressing an ALS-causing gene in oligodendrocytes of mice bred with the disease — while still allowing the gene to remain in the motor neurons — profoundly delayed the onset of ALS. It also prolonged survival of these mice by more than three months, a long time in the life span of a mouse. These observations suggest that oligodendrocytes play a very significant role in the early stage of the disease.

“The abnormalities in oligodendrocytes appear to be having a negative impact on the survival of motor neurons,” says Dwight E. Bergles, Ph.D., a co-author and a professor of neuroscience at the Johns Hopkins University School of Medicine. “The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn’t appreciate before.”

“These findings teach us that cells we never thought had a role in ALS not only are involved but also clearly contribute to the onset of the disease,” says co-author Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology at Johns Hopkins and director of the Johns Hopkins Medicine Brain Science Institute.

Scientists have long believed that oligodendrocytes functioned only as structural elements of the central nervous system. They wrap around nerves, making up the myelin sheath that provides the “insulation” that allows nerve signals to be transmitted rapidly and efficiently. However, Rothstein and others recently discovered that oligodendrocytes also deliver essential nutrients to neurons, and that most neurons need this support to survive.

The Johns Hopkins team of Bergles and Rothstein published a paper in 2010 that described in mice with ALS an unexpected massive proliferation of oligodendrocyte progenitor cells in the spinal cord’s motor neurons, and that these progenitors were being mobilized to make new oligodendrocytes. The researchers believed that these cells were multiplying because of an injury to oligodendrocytes, but they weren’t sure what was happening. Using a genetic method of tracking the fate of oligodendrocytes, in the new study, the researchers found that cells present in young mice with ALS were dying off at an increasing rate in concert with advancing disease. Moreover, the development of the newly formed oligodendrocytes was stalled and they were not able to provide motor neurons with a needed source of cell nutrients.

To determine whether the changes to the oligodendrocytes were just a side effect of the death of motor neurons, the scientists used a poison to kill motor neurons in the ALS mice and found no response from the progenitors, suggesting, says Rothstein, that it is the mutant ALS gene that is damaging oligodendrocytes directly.

Meanwhile, in separate experiments, the researchers found similar changes in samples of tissues from the brains of 35 people who died of ALS. Rothstein says it may be possible to see those changes early on in the disease and use MRI technology to follow progression.

“If our research is confirmed, perhaps we can start looking at ALS patients in a different way, looking for damage to oligodendrocytes as a marker for disease progression,” Rothstein says. “This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working.”

ALS, also known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, affects nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary.

There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival.

Even though myelin loss has not previously been thought to occur in the gray matter, a region in the brain where neurons process information, the researchers in the new study found in ALS patients a significant loss of myelin in one of every three samples of human tissue taken from the brain’s gray matter, suggesting that the oligodendrocytes were abnormal. It isn’t clear if the oligodendrocytes that form this myelin in the gray matter play a different role than in white matter — the region in the brain where signals are relayed.

The findings further suggest that clues to the treatment of other diseases long believed to be focused in the brain’s gray matter — such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease — may be informed by studies of diseases of the white matter, such as multiple sclerosis (MS). Bergles says ALS and MS researchers never really thought their diseases had much in common before.

Oligodendrocytes have been under intense scrutiny in MS, Bergles says. In MS, the disease over time can transform from a remitting-relapsing form — in which myelin is attacked but then is regenerated when existing progenitors create new oligodendrocytes to re-form myelin — to a more chronic stage in which oligodendrocytes are no longer regenerated. MS researchers are working to identify new ways to induce the creation of new oligodendrocytes and improve their survival. “It’s possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS,” Bergles says.

(Source: newswise.com)

The British astrophysicist Stephen Hawking is likely to be the world’s most famous person living with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. ALS is a progressive disease affecting motor neurons, nerve cells that control muscle function, and nearly always leads to death. Researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna have now identified a completely new mechanism in the onset of motor neuron diseases. Their findings could be the basis for future treatments for these presently incurable diseases.

A new principle on motor neuron death
The IMBA scientists, working with an international team of researchers under the leadership of Josef Penninger and Javier Martinez, discovered a completely new fundamental mechanism that triggers the death of motor neurons. Motor neurons are nerve cells responsible for stimulating muscles. The loss of these motor neurons in mice with a genetic mutation in a gene named CLP11 leads to severe and progressive muscular paralysis and, in some cases, to death.
"We’ve been working on resolving the function of the CLP1 gene in a living organism for a long time. To do that, we developed model mice in which the function of CLP1 was genetically inactivated. To our utter surprise we discovered that deactivating CLP1 increases the sensitivity of cell die when exposed to oxidative stress2. That leads to enhanced activity of the p53 protein3 and then to the permanent destruction of motor neurons," says Toshikatsu Hanada, a postdoctoral researcher working in the lab of Josef Penninger and first author of the study along with Stefan Weitzer.

Stephen Hawking - a most renowned patient
Motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are chronic disorders of the neuromuscular system. These diseases are caused by damage in the motor nerve cells in the brain and spinal cord, and the nerves can no longer stimulate motion in the muscles. The primary symptoms are muscular weakness, muscular dystrophy, and problems swallowing or speaking. Stephen Hawking was diagnosed with ALS 50 years ago. But not all ALS patients live so long with the disease: so far there are no treatments for ALS. Nearly all ALS patients die of paralysis of respiratory muscles within a few years.

Completely new disease mechanism
Javier Martinez, an IMBA team leader and co-author of the study, is a specialist in the field of ribonucleic acid (RNA) research. His research group had discovered the CLP1 gene in an earlier study, published in Nature in 2007. Until now, the exact essential function of CLP1 in RNA biology was unclear. “By deactivating CLP1, we have discovered a previously unknown new species of RNA,” says Javier Martinez about the scientific relevance of the work. “The accumulation of this RNA is a consequence of increased oxidative stress in the cell. We see this as one of the triggers for the loss of motor neurons that occurs in ALS and other neuromuscular diseases. Thus our findings describe a completely new mechanism of motor neuron diseases.”

Seminal findings
Josef Penninger, scientific director at the IMBA and last-author of the study, is excited about the researchers’ findings: “This surprising discovery of a role of CLP1 in the onset of motor neuron diseases is an entirely new principle in how RNA talks to oxidative stress. Nearly all genetic mutations found in ALS patients affect either RNA metabolism or oxidative stress, suggesting a possibly unifying principle for these diseases. Our work may have revealed the ‘missing link’ in how these two biological systems communicate and trigger incurable diseases like ALS.”

Stefan Weitzer sees tremendous potential for these findings: “We’ve discovered a new mechanism that leads to the death of motor neurons. If this holds true for other neuronal disease, our results could be one day used to drive the development of treatments for previously incurable diseases. In our work we also describe how the p53 protein regulates the loss of motor neurons. Removing p53 saves mice with CLP1 mutations from certain death.” If scientists are successful in applying these findings to people, the researchers may have discovered a treatment approach to cure ALS and similar diseases. The authors, however, caution that more studies will be needed to translate their findings to human medicine.

This study was performed in collaboration with research groups from the Medical Universities of Vienna and Innsbruck, the University Medical Center at Hamburg-Eppendorf in Germany, the Harvard Medical School, the Harvard Stem Cell Institute, the Boston Children’s and Massachusetts General Hospitals, the Keio University School of Medicine in Tokyo, Oita University in Japan, and the Weizmann Institute of Science in Rehovot in Israel.

Their work, “CLP1 links tRNA metabolism to progressive motor-neuron loss”, was published on March 10, 2013 in “Nature”, an internationally renowned journal.

(Source: imba.oeaw.ac.at)