Posts tagged ALS

Although the technology has existed for just a few years, scientists increasingly use “disease in a dish” models to study genetic, molecular and cellular defects. But a team of doctors and scientists led by researchers at the Cedars-Sinai Regenerative Medicine Institute went further in a study of Lou Gehrig’s disease, a fatal disorder that attacks muscle-controlling nerve cells in the brain and spinal cord.

After using an innovative stem cell technique to create neurons in a lab dish from skin scrapings of patients who have the disorder, the researchers inserted molecules made of small stretches of genetic material, blocking the damaging effects of a defective gene and, in the process, providing “proof of concept” for a new therapeutic strategy – an important step in moving research findings into clinical trials.

The study, published Oct. 23 in Science Translational Medicine, is believed to be one of the first in which a specific form of Lou Gehrig’s disease, or amyotrophic lateral sclerosis, was replicated in a dish, analyzed and “treated,” suggesting a potential future therapy all in a single study.

"In a sense, this represents the full spectrum of what we are trying to accomplish with patient-based stem cell modeling. It gives researchers the opportunity to conduct extensive studies of a disease’s genetic and molecular makeup and develop potential treatments in the laboratory before translating them into patient trials," said Robert H. Baloh, MD, PhD, director of Cedars-Sinai’s Neuromuscular Division in the Department of Neurology and director of the multidisciplinary ALS Program. He is the lead researcher and the article’s senior author.

Laboratory models of diseases have been made possible by a recently invented process using induced pluripotent stem cells – cells derived from a patient’s own skin samples and “sent back in time” through genetic manipulation to an embryonic state. From there, they can be made into any cell of the human body.

The cells used in the study were produced by the Induced Pluripotent Stem Cell Core Facility of Cedars-Sinai’s Regenerative Medicine Institute. Dhruv Sareen, PhD, director of the iPSC facility and a faculty research scientist with the Department of Biomedical Sciences, is the article’s first author and one of several institute researchers who participated in the study.

"In these studies, we turned skin cells of patients who have ALS into motor neurons that retained the genetic defects of the disease," Baloh said. "We focused on a gene, C9ORF72, that two years ago was found to be the most common cause of familial ALS and frontotemporal lobar degeneration, and even causes some cases of Alzheimer’s and Parkinson’s disease. What we needed to know, however, was how the defect triggered the disease so we could find a way to treat it."

Frontotemporal lobar degeneration is a brain disorder that typically leads to dementia and sometimes occurs in tandem with ALS.

The researchers found that the genetic defect of C9ORF72 may cause disease because it changes the structure of ribonucleic acid (RNA) coming from the gene, creating an abnormal buildup of a repeated set of nucleotides, the basic components of RNA.

"We think this buildup of thousands of copies of the repeated sequence GGGGCC in the nucleus of patients’ cells may become "toxic" by altering the normal behavior of other genes in motor neurons," Baloh said. "Because our studies supported the toxic RNA mechanism theory, we used two small segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and degrade the toxic RNA. One ASO knocked down overall C9ORF72 levels. The other knocked down the toxic RNA coming from the gene without suppressing overall gene expression levels. The absence of such potentially toxic RNA, and no evidence of detrimental effect on the motor neurons, provides a strong basis for using this strategy to treat patients suffering from these diseases."

Researchers from another institution recently led a phase one trial of a similar ASO strategy to treat ALS caused by a different genetic mutation and reportedly uncovered no safety issues.

(Source: cedars-sinai.edu)

Johns Hopkins scientists have developed new drugs that — at least in a laboratory dish — appear to halt the brain-destroying impact of a genetic mutation at work in some forms of two incurable diseases, amyotrophic lateral sclerosis (ALS) and dementia.

They made the finding by using neurons they created from stem cells known as induced pluripotent stem cells (iPS cells), which are derived from the skin of people with ALS who have a gene mutation that interferes with the process of making proteins needed for normal neuron function.

“Efforts to treat neurodegenerative diseases have the highest failure rate for all clinical trials,” says Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and leader of the research described online in the journal Neuron. “But with this iPS technology, we think we can target an exact subset of patients with a specific mutation and succeed. It’s individualized brain therapy, just the sort of thing that has been done in cancer, but not yet in neurology.”

Scientists in 2011 discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the non-inherited sporadic form have a mutation in the C9ORF72 gene. The mutation also occurs very often in people with frontotemporal dementia, the second-most-common form of dementia after Alzheimer’s disease. The same research appeared to explain why some people develop both ALS and the dementia simultaneously and that, in some families, one sibling might develop ALS while another might develop dementia.

In the C9ORF72 gene of a normal person, there are up to 30 repeats of a series of six DNA letters (GGGGCC); but in people with the genetic glitch, the string can be repeated thousands of times. Rothstein, who is also director of the Johns Hopkins Brain Science Institute and the Robert Packard Center for ALS Research, used his large bank of iPS cell lines from ALS patients to identify several with the C9ORF72 mutation, then experimented with them to figure out the mechanism by which the “repeats” were causing the brain cell death characteristic of ALS.

In a series of experiments, Rothstein says, they discovered that in iPS neurons with the mutation, the process of using the DNA blueprint to make RNA and then produce protein is disrupted. Normally, RNA-binding proteins facilitate the production of RNA. Instead, in the iPS neurons with the C9ORF72 mutation, the RNA made from the repeating GGGGCC strings was bunching up, gumming up the works by acting like flypaper and grabbing hold of the extremely important RNA binding proteins, including one known as ADARB2,  needed for the proper production of many other cellular RNAs. Overall, the C9ORF72 mutation made the cell produce abnormal amounts of many other normal RNAs and made the cells very sensitive to stress.

To counter this effect, the researchers developed a number of chemical compounds targeting the problem. This compound behaved like a coating that matches up to the GGGGCC repeats like velcro, keeping the flypaper-like repeats from attracting the bait, allowing the RNA-binding protein to properly do its job.

Rothstein says Isis Pharmaceuticals helped develop many of the studied compounds and, by working closely with the Johns Hopkins teams, could begin testing it in human ALS patients with the C9ORF72 mutation in the next several years. In collaboration with the National Institutes of Health, plans are already underway to begin to identify a group of patients with the C9ORF72 mutation for future research.

Rita Sattler, Ph.D., an assistant professor of neurology at Johns Hopkins and the co-investigator of the study, says without iPS technology, the team would have had a difficult time studying the C9ORF72 mutation. “Typically, researchers engineer rodents with mutations that mimic the human glitches they are trying to research and then study them,” she says. “But the nature of the multiple repeats made that nearly impossible.” The iPS cells did the job just as well or even better than an animal model, Sattler says, in part because the experiments could be done using human cells.

“An iPS cell line can be used effectively and rapidly to understand disease mechanisms and as a tool for therapy development,” Rothstein adds. “Now we need to see if our findings translate into a valuable treatment for humans.”

The researchers also analyzed brain tissue from people with the C9ORF72 mutation who died of ALS. They saw evidence of this bunching up and found that the many genes that were altered as a consequence of this mutation in the iPS cells were also abnormal in the brain tissue, thereby showing that iPS cells can be a faithful tool to study the human disease and discover effective therapies.

In the future, the scientists will look at cerebral spinal fluid from ALS patients with the C9ORF72 mutation, searching for proteins that were found both in the fluid and the iPS cells. These may pave the way to develop markers that can be studied by clinicians to see if the treatment is working once the drug therapy is moved to clinical trials.

ALS, sometimes known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, destroys 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, Rothstein notes.

(Source: hopkinsmedicine.org)

New research from the University of Sheffield could offer solutions into slowing down the progression of motor neurone disease (MND).

Scientists from the University of Sheffield’s Institute for Translational Neuroscience (SITraN) conducted pioneering research assessing how the devastating debilitating disease affects individual patients.

MND is an incurable disease destroying the body’s cells which control movement causing progressive disability. Present treatment options for those with MND only have a modest effect in improving the patient’s quality of life.

Professor Pamela Shaw, Director of SITraN, and her research team worked in collaboration with a fellow world leading MND scientist Dr Caterina Bendotti and her group at the Mario Negri Institute for Pharmacological Research in Milan, Italy. Together they investigated why the progression of MND following onset of symptoms varies in speed, even in the presence of a known genetic cause of the condition.

The research, published in the scientific journal Brain, investigated two mouse models of MND caused by an alteration in the SOD1 gene, a known cause of MND in humans. One of the strains had a rapidly progressing disease course and the other a much slower change in the symptoms of MND. The teams from Sheffield and Milan looked at the factors which might explain the differences observed in speed and severity in the progression of the disease. They used a scientific technique known as gene expression profiling to identify factors within motor neurones that control vulnerability or resistance to MND in order to shed light on the factors important for the speed of motor neurone injury in human patients.

The study, funded by the Motor Neurone Disease Association, revealed new evidence, at the point of onset of the disease, before muscle weakness was observed, showing key differences in major molecular pathways and the way the protective systems of the body responded, between the profiles of the rapid progressing and slow progressing mouse models. In the case of the model with rapidly progressing MND the motor neurones showed reduced functioning of the cellular systems for energy production, disposal of waste proteins and neuroprotection. Motor neurones from the model with more slowly progressing MND showed an increase in protective inflammation and immune responses and increased function of the mechanisms that protect motor neurones from damage.

The research provides valuable clues about mechanisms that have the effect of slowing down the progression of disabling symptoms in MND.

Professor Shaw said that the state-of-the-art Functional Genomics laboratory in SITraN had enabled the research team to use a cutting edge technique called gene expression profiling.
“This enables us to ‘get inside’ the motor neurones in health and disease and understand better what is happening to cause motor neurone injury in MND,” she said.

“This project was a wonderful collaboration, supported by the MND Association, between research teams in Sheffield and Milan. We are very excited about the results which have given us some new ideas for treatment strategies which may help to slow disease progression in human MND.”

Dr Caterina Bendotti said: “MND is a clinically heterogenous disease with a high variability in its course which makes assessments of potential therapies difficult. Thanks to the recent evidence in our laboratory of a difference in the speed of symptom progression in two MND models carrying the same gene mutation and the successful collaboration with Professor Pamela Shaw and her team, we have identified some mechanisms that may help to predict the disease duration and eventually to slow it down.

“I strongly believe that the new hypotheses generated by this study and our ongoing collaboration are the prerequisites to be able to fight this disease.”

Brian Dickie from MND Association added: “These new and important findings in mice open up the possibility for new treatment approaches in man. It is heartening to see such a productive collaboration between two of the leading MND research labs in Europe, combining their unique specialist knowledge and technical expertise in the fight against this devastating disease.”

MND affects more than 6,000 sufferers in the UK with the majority of cases being sporadic but approximately five per cent of cases are familial or inherited with an identifiable genetic cause. Sufferers may lose their ability to walk, talk, eat and breathe.

(Source: sheffield.ac.uk)

Proteins play important roles in the human body, particularly neuroproteins that maintain proper brain function.

Brain diseases such as ALS, Alzheimer’s, and Parkinson’s are known as “tangle diseases” because they are characterized by misfolded and tangled proteins which accumulate in the brain.

A team of Australian and American scientists discovered that an unusual amino acid called BMAA can be inserted into neuroproteins, causing them to misfold and aggregate. BMAA is produced by cyanobacteria, photosynthetic bacteria that form scums or mats in polluted lakes or estuaries.

BMAA has been detected in the brain tissues of ALS patients.

In an article published in PLOS ONE scientists at the University of Technology Sydney and the Institute for Ethnomedicine in Jackson Hole, Wyoming, report that BMAA mimics a dietary aminoacid, L-Serine, and is mistakenly incorporated into neuroproteins, causing the proteins to misfold. The misfolded proteins build up in cells, eventually killing them.

"We found that BMAA inserts itself by seizing the transfer RNA for L-Serine. This, in essence, puts a kink in the protein causing it to misfold," says lead author Dr. Rachael Dunlop, a cell biologist in Sydney working in the laboratory of Dr. Ken Rodgers.

"The cells then begin programmed cell death, called apoptosis. "Even more importantly, the scientists found that extra L-Serine added to the cell culture can prevent the insertion of BMAA into neuroproteins. The possibility that L-Serine could be used to prevent or slow ALS is now being studied."

Even though L-serine occurs in our diet, its safety and efficacy for ALS patients should be properly determined through FDA-approved clinical trials before anyone advocates its use,” says American co-author Dr. Paul Cox.

In ALS, motor neurons in the brain and spinal cord die, progressively paralyzing the body until even swallowing and breathing becomes impossible.

The disease is relatively rare but has affected a number of high-profile people including Professor Stephen Hawking and Yankee baseball player Lou Gehrig.

"For many years scientists have linked BMAA to an increased risk of motor neuron disease but the missing pieces of the puzzle relate to how this might occur. Finally, we have one of those pieces," said Dr Sandra Banack, a co-author on the paper.

(Source: eurekalert.org)

University of Adelaide researchers have identified a likely molecular pathway that causes a group of untreatable neurodegenerative diseases, including Huntington’s disease and Lou Gehrig’s disease.

The group of about 20 diseases, which show overlapping symptoms that typically include nerve cell death, share a similar genetic mutation mechanism ‒ but how this form of mutation causes these diseases has remained a mystery.

"Despite the genes for some of these diseases having been identified 20 years ago, we still haven’t understood the underlying mechanisms that lead to people developing clinical symptoms," says Professor Robert Richards, Head of Genetics in the University’s School of Molecular and Biomedical Sciences.

"By uncovering the molecular pathway for these diseases, we now expect to be able to define targets for intervention and so come up with potential therapies. Ultimately this will help sufferers to reduce the amount of nerve cell degeneration or slow its progression."

In an article published in Frontiers in Molecular Neuroscience, Professor Richards and colleagues describe their innovative theory and new evidence for the key role of RNA in the development of the diseases. RNA is a large molecule in the cell that copies genetic code from the cell’s DNA and translates it into the proteins that drive biological functions.

People with these diseases all have expanded numbers of copies of particular sequences of the ‘nucleotide bases’ which make up DNA.

"In most cases people with these diseases have increased numbers of repeat sequences in their RNA," says Professor Richards. "The disease develops when people have too many copies of the repeat sequence. Above a certain threshold, the more copies they have the earlier the disease develops and the more severe the symptoms. The current gap in knowledge is why having these expanded repeat sequences of genes in the RNA translates into actual symptoms."

Professor Richards says evidence points towards a dysfunctional RNA and a pivotal role of the body’s immune system in the development of the disease.

"Rather than recognising the ‘expanded repeat RNA’ as its own RNA, we believe the ‘expanded repeat RNA’ is being seen as foreign, like the RNA in a virus, and this activates the innate immune system, resulting in loss of function and ultimately the death of the cell," he says.

The University of Adelaide laboratory modelled and defined the expanded repeat RNA disease pathway using flies (Drosophila). Other laboratories have reported tell-tale, but previously inexplicable, signs characteristic of this pathway in studies of patients with Huntington’s disease and Myotonic Dystrophy.

"This new understanding, once proven in each of the relevant human diseases, opens the way for potential treatments, and should give cause for hope to those with these devastating diseases," Professor Richards says.

(Source: adelaide.edu.au)

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)

Study strengthens link between amyotrophic lateral sclerosis (ALS) and problems in protein production machinery of cells and identifies possible treatment strategy

Researchers have tied mutations in a gene that causes amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders to the toxic buildup of certain proteins and related molecules in cells, including neurons. The research, published recently in the scientific journal Cell, offers a new approach for developing treatments against these devastating diseases.

Scientists at St. Jude Children’s Research Hospital and the University of Colorado, Boulder, led the work.

The findings provide the first evidence that a gene named VCP plays a role in the break-up and clearance of protein and RNA molecules that accumulate in temporary structures called RNA granules. RNAs perform a variety of vital cell functions, including protein production. RNA granules support proper functioning of RNA.

In ALS and related degenerative diseases, the process of assembling and clearing RNA granules is impaired. The proteins and RNAs associated with the granules often build up in nerve cells of patients. This study shows how mutations in VCP might contribute to that process and neurodegenerative disease.

“The results go a long way to explaining the process that links a variety of neurodegenerative diseases, including ALS, frontotemporal dementia and related diseases of the brain, muscle and bone known as multisystem proteinopathies,” said the study’s co-corresponding author, J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. Roy Parker, Ph.D., of the University of Colorado’s Department of Chemistry and Biochemistry and the Howard Hughes Medical Institute (HHMI), is the other corresponding author.

ALS, also known as Lou Gehrig’s disease, is diagnosed in about 5,600 Americans annually and is associated with progressive deterioration of nerve cells in the brain and spine that govern movement, including breathing. There is no effective treatment, and death usually occurs within five years.

“A strength of this study is that it provides a unifying hypothesis about how different genetic mutations all affect stress granules, which suggests that understanding stress granule dynamics and how they can be manipulated might be beneficial for treatment of these diseases,” Parker said.

Earlier work from Taylor’s laboratory identified mutations in VCP as a cause of ALS and related multisystem proteinopathies. Until now, however, little was known about how those mistakes caused disease. The latest findings appeared in the June 20 issue and are highlighted in a review article published in the August 15 issue of Cell.

The research also ties VCP mutations to disruption of RNA regulation, which prior studies have connected to the progression of neurodegenerative diseases, said Regina-Maria Kolaitis, Ph.D., a postdoctoral fellow in Taylor’s laboratory. She and Ross Buchan, Ph.D., a postdoctoral fellow in Parker’s laboratory, are co-first authors.

The work focused on a class of RNA granules called stress granules. They are formed by proteins and an RNA molecule called mRNA that accumulates in the cell cytoplasm in response to stress. Stressed cells do not want to waste energy producing unnecessary proteins. Stress granules are one mechanism cells use to halt production until the cellular environment normalizes, which is when stress granules typically dissolve.

Proteins found in stress granules include RNA-binding proteins like TDP-43, FUS, hnRNPA1 and hnRNPA2B1 that regulate gene activity. Mutations in those proteins can also cause ALS and related disorders.

“VCP has many functions in cells, but it is not an RNA-binding protein and until now it was not connected to stress granules or RNA processing,” Kolaitis said. “This study provides a new window into the disease process, highlighting VCP’s role in keeping cells healthy.”

For this study, researchers used yeast to identify a network of 125 genes that affect the formation and behavior of stress granules. One of the genes that appeared to play a central role in the network was CDC48, which functions like VCP in yeast. In addition, many of the genes identified are involved in a process called autophagy that cells use to break down and recycle unneeded molecules, including proteins.

Working in yeast and mammalian cells, researchers showed that stress granules are cleared by autophagy, which stalled when VCP was mutated. Researchers also reported that stress granules accumulated following mutation of either CDC48 or VCP.

“This work suggests that activating autophagy to help rid cells of stress granules offers a new approach to neurodegenerative disease treatment,” Taylor said.

(Source: stjude.org)

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease that rapidly atrophies the muscles, leading to complete paralysis. Despite its high profile — established when it afflicted the New York Yankees’ Lou Gehrig — ALS remains a disease that scientists are unable to predict, prevent, or cure.

Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.

Now, using samples of stem cells derived from the bone marrow of non-genetic ALS patients, Prof. Miguel Weil of Tel Aviv University’s Laboratory for Neurodegenerative Diseases and Personalized Medicine in the Department of Cell Research and Immunology and his team of researchers have uncovered four different biomarkers that characterize the non-genetic form of the disease. Each sample shows similar biological abnormalities to four specific genes, and further research could reveal additional commonalities. “Because these genes and their functions are already known, they give us a specific direction for research into non-genetic ALS diagnostics and therapeutics,” Prof. Weil says. His initial findings were reported in the journal Disease Markers.

Giving in to stress

To hunt for these biomarkers, Prof. Weil and his colleagues turned to samples of bone marrow collected from ALS patients. Though more difficult to collect than blood, bone marrow’s stem cells are easy to isolate and grow in a consistent manner. In the lab, he used these cells as cellular models for the disease. He ultimately discovered that cells from different ALS patients shared the same abnormal characteristics of four different genes that may act as biomarkers of the disease. And because the characteristics appear in tissues that are related to ALS — including in muscle, brain, and spinal cord tissues in mouse models of genetic ALS — they may well be connected to the degenerative process of the disease in humans, he believes.

Searching for the biological significance of these abnormalities, Prof. Weil put the cells under stress, applying toxins to induce the cells’ defense mechanisms. Healthy cells will try to fight off threats and often prove quite resilient, but ALS cells were found to be overwhelmingly sensitive to stress, with the vast majority choosing to die rather than fight. Because this is such an ingrained response, it can be used as a feature for drug screening for the disease, he adds.

The hunt for therapeutics

Whether these biomarkers are a cause or consequence of ALS is still unknown. However, this finding remains an important step towards uncovering the mechanisms of the disease. Because these genes have already been identified, it gives scientists a clear direction for future research. In addition, these biomarkers could lead to earlier and more accurate diagnostics.

Next, Prof. Weil plans to use his lab’s high-throughput screening facility — which can test thousands of compounds’ effects on diseased cells every day — to search for drug candidates with the potential to affect the abnormal expression of these genes or the stress response of ALS cells. A compound that has an impact on these indicators of ALS could be meaningful for treating the disease, he says.

Prof. Weil is the director of the new Cell Screening Facility for Personalized Medicine at TAU. The facility is dedicated to finding potential drugs for rare and Jewish hereditary diseases.

(Source: aftau.org)