Posts tagged Lou Gehrig's disease

Measuring changes in certain proteins — called biomarkers — in people with amyotrophic lateral sclerosis may better predict the progression of the disease, according to scientists at Penn State College of Medicine.

ALS is often referred to as Lou Gehrig’s disease, is a neurological disease in which the brain loses its ability to control movement as motor neurons degenerate. The course of the disease varies, with survival ranging from months to decades.

"The cause of most cases of ALS remains unknown," said James Connor, Distinguished Professor of Neurosurgery, Neural and Behavioral Sciences and Pediatrics. "Although several genetic and environmental factors have been identified, each accounts for only a fraction of the total cases of ALS."

This clinical variation in patients presents challenges in terms of managing the disease and developing new treatments. Finding relevant biomarkers, which are objective measures that reflect changes in biological processes or reactions to treatments, may help address these challenges.

The project was led by Xiaowei Su, an M.D./ Ph.D. student in Connor’s laboratory, in collaboration with Zachary Simmons, director of the Penn State Hershey ALS Clinic and Research Center. Su studied plasma and cerebrospinal fluid samples previously collected from patients undergoing diagnostic evaluation, who were later identified as having ALS. Analysis shows that looking at multiple biomarkers to predict progression is not only mathematically possible, it improves upon methods using single biomarkers.

Statistical models analyzing plasma had reasonable ability to predict total disease duration and used seven relevant biomarkers. For example, higher levels of the protein IL-10 predict a longer disease duration. IL-10 is involved with anti-inflammation, suggesting that lower levels of inflammation are associated with a longer disease duration.

The researchers identified six biomarkers for cerebrospinal fluid. For example, higher levels of G-CSF — a growth factor known to have protective effects on motor neurons, the cells that die in ALS — predicts a longer disease duration.

Perhaps most importantly, the results suggest that a combination of biomarkers from both plasma and cerebrospinal fluid better predict disease duration.

While the size of this study is small, the ability of the specific biomarkers used to predict prognosis suggests that the approach holds promise.

"The results argue for the usefulness of researching this approach for ALS both in terms of predicting disease progression and in terms of determining the impact of therapeutic strategies," Connor said. "The results present a compelling starting point for the use of this method in larger studies and provide insights for novel therapeutic targets."

(Source: news.psu.edu)

Researchers at the Stanford University School of Medicine have identified mutations in several new genes that might be associated with the development of spontaneously occurring cases of the neurodegenerative disease known as amyotrophic lateral sclerosis, or ALS. Also known as Lou Gehrig’s disease, the progressive, fatal condition, in which the motor neurons that control movement and breathing gradually cease to function, has no cure.

Although researchers know of some mutations associated with inherited forms of ALS, the majority of patients have no family history of the disease, and there are few clues as to its cause. The Stanford researchers compared the DNA sequences of 47 patients who have the spontaneous form of the disease, known as sporadic ALS, with those of their unaffected parents. The goal was to identify new mutations that were present in the patient but not in either parent that may have contributed to disease development.

Several suspects are mutations in genes that encode chromatin regulators — cellular proteins that govern how DNA is packed into the nucleus of a cell and how it is accessed when genes are expressed. Protein members of one these chromatin-regulatory complexes have recently been shown to play roles in normal development and some forms of cancer.

"The more we know about the genetic causes of the disorder, the greater insight we will have as to possible therapeutic targets," said Aaron Gitler, PhD, associate professor of genetics. "Until now, researchers have primarily relied upon large families with many cases of inherited ALS and attempted to pinpoint genetic regions that seem to occur only in patients. But more than 90 percent of ALS cases are sporadic, and many of the genes involved in these cases are unknown."

Gitler is the senior author of the study, published online May 26 in Nature Neuroscience. Postdoctoral scholar Alessandra Chesi, PhD, is the lead author. Gitler and Chesi collaborated with members of the laboratory of Gerald Crabtree, MD, professor of developmental biology and of pathology. Crabtree, a Howard Hughes Medical Institute investigator, is also a co-author of the study.

Chesi and Gitler combined deductive reasoning with recent advances in sequencing technology to conduct the work, which relied on the availability of genetic samples from not only ALS patients, but also the patients’ unaffected parents. Such trios can be difficult to obtain for diseases like sporadic ALS that strike well into adulthood when a patient’s parents may no longer be alive. Gitler and Chesi collaborated with researchers from Emory University and Johns Hopkins University to collect these samples.

The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient’s exome, but not in that of his or her parents’, were viewed as potential disease-associated candidates - particularly if they affected the composition or structure of the resulting protein made from that gene.

Focusing on just the exome, which is about 1 percent of the total amount of DNA in each human cell, vastly reduced the total amount of DNA that needed to be sequenced and allowed the researchers to achieve relatively high coverage (or repeated sequencing to ensure accuracy) of each sample.

"We wanted to find novel changes in the patients," Chesi said. "These represent a class of mutations called de novo mutations that likely occurred during the production of the parents’ reproductive cells." As a result, these mutations would be carried in all the cells of patients, but not in their parents or siblings.

Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin — a proportion that is much higher than would have been expected by chance, according to Chesi.

Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree’s laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.

"We found that, in one sporadic ALS case, the last nine amino acids of this protein are missing," Gitler said. "I knew that Gerald Crabtree’s lab had been investigating SS18L1, so I asked him about it. In fact, they had already identified these amino acids as being very important to the function of the protein."

When the researchers expressed the mutant SS18L1 in motor neurons isolated from mouse embryos, they found the neurons were unable to extend and grow new dendrites as robustly as normal neurons in response to stimuli. They also showed that SS18L1 appears to physically interact with another protein known to be involved in cases of familial, or inherited, ALS.

Although the results are intriguing, the researchers caution that more work is necessary to conclusively prove whether and how mutations in SS18L1 contribute to sporadic cases of ALS. But now they have an idea of where to look in other patients, without requiring the existence of patient and parent trios. They are planning to sequence SS18L1 and other candidates in an additional few thousand sporadic ALS cases.

"This is the first systematic analysis of ALS triads for the presence of de novo mutations," Chesi said. "Now we have a list of candidate genes we can pursue. We haven’t proven that these mutations cause ALS, but we’ve shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites."

(Source: med.stanford.edu)

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)

Melatonin injections delayed symptom onset and reduced mortality in a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a new study by researchers at the University of Pittsburgh School of Medicine. In a report published online ahead of print in the journal Neurobiology of Disease, the team revealed that receptors for melatonin are found in the nerve cells, a finding that could launch novel therapeutic approaches.

Annually about 5,000 people are diagnosed with ALS, which is characterized by progressive muscle weakness and eventual death due to the failure of respiratory muscles, said senior investigator Robert Friedlander, M.D., UPMC Endowed Professor of neurosurgery and neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But the causes of the condition are not well understood, thwarting development of a cure or even effective treatments.

Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. After screening more than a thousand FDA-approved drugs several years ago, the research team determined that melatonin is a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.

"Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS," Dr. Friedlander said. "We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases."

Hoping to stop neuron death in ALS just as they did in Huntington’s, the research team treated mice bred to have an ALS-like disease with injections of melatonin or with a placebo. Compared to untreated animals, the melatonin group developed symptoms later, survived longer, and had less degeneration of motor neurons in the spinal cord.

"Much more work has to be done to unravel these mechanisms before human trials of melatonin or a drug akin to it can be conducted to determine its usefulness as an ALS treatment," Dr. Friedlander said. "I suspect that a combination of agents that act on these pathways will be needed to make headway with this devastating disease."

(Source: eurekalert.org)

A team led by Dr. Alex Parker, a professor of pathology and cellular biology and a researcher at the University of Montreal Hospital Research Centre (CRCHUM), has identified an important therapeutic target for alleviating the symptoms of Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis (ALS), and other related neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

In a study published in the online version of Neurobiology of Disease, the team both confirmed the importance of this new target as well as a series of compounds that can be used to attenuate the dysregulation of one of the important cellular processes that lead to neuronal dysfunction and ultimately to brain cell death.

Although scientists are unclear about causes of ALS, they have made headway in identifying the cellular process potentially implicated in disease onset and progression. One such process which has attracted researcher interest involves the endoplasmic reticulum (ER), a component of cells that plays an important role in maintaining cell health. In collaboration with Dr. Pierre Drapeau at the University of Montreal and using worm and zebrafish models of ALS, Parker’s team not only confirmed that incapacitated ER leads to the motor neuron death typical of ALS, but also identified a series of compounds that alleviate the fatal consequences of defective ER.

“Since Riluzole, the one approved treatment compound for treating ALS, only has a modest effect on slowing disease progression, we set out to test a number of other compounds, and in so doing we discovered that they work by compensating for defective ER” explains Dr Parker. The compounds in question, Methylene blue, Salubrinal, Guanabenz and Phenazine, were each tested individually and in different combinations.

With the exception of Phenazine, these compounds have known benefits for treating neurodegenerative diseases. Parker and his team showed that each of these compounds reduces paralysis and neurodegeneration and that each acts on different parts of the ER pathway to achieve neuroprotection. More importantly, the researchers found that using these compounds in different combinations can enhance their therapeutic effects.

“These results are quite encouraging,” says Dr Parker, “and have given us a much better understanding of ER’s role in ALS as well as showing the way for improved treatments”. Parker’s team plans to test and confirm these findings with more complex animal models, a necessary step in developing medication that can be of benefit to human beings.

(Source: nouvelles.umontreal.ca)

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)