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By Brooke Adams The mice at the top of a column of stacked plastic bins at Q Therapeutics are shivering so hard they seem to be jumping. Their nonstop shivering and seizures are caused by a genetic defect that robs the mice of the crucial myelin sheath that surrounds nerve cells and helps them send signals. Because of the defect, the mice are soon paralyzed and die prematurely. It is a related problem -- loss of this myelin sheath -- that in humans causes the progressive loss of function in multiple sclerosis and several other diseases that can cause paralysis in humans. And that's why what has happened to the mice is so promising: After being treated with an adult stem cell therapy developed at Q Therapeutics, they are no longer shivering. The product, called Q-Cells, also may be applicable to such neurodegenerative diseases as Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, or ALS -- better known as Lou Gehrig's disease. Now, the National Institutes of Health have awarded a $5 million grant to Q Therapeutics, the University of Utah's Cell Therapy Facility and Johns Hopkins University School of Medicine, which as a team has had success in animal models of ALS.
Scientists have identified a protective gene that increases survival in motor neuron disease. People with the KIFAP3 gene lived 14 months longer on average than other MND patients. Experts hope they will be able to use this knowledge to develop life-extending treatments for patients with this debilitating and fatal disease. So far, one drug, riluzole, has been proven to extend life expectancy, but only by a few months. MND attacks the nerves that control movement and is often rapidly progressive. The vast majority of people with MND die within two to five years. Half of people die within 14 months of diagnosis. The researchers wanted to find out why a small minority appear to be more resistant to the disease. To do this they looked at 300,000 genetic variants in 2,359 people with MND and 2,814 unaffected volunteers from six different countries. They found that people with two beneficial variants of KIFAP3 lived on average four years while those with only one or none lived on average for two years and eight months. This improved the chances of surviving five years from about 10% to more than 30% for those carrying the "good" variants of KIFAP3. Lead researcher Professor Ammar Al-Chalabi, of King's College London, said scientists would now be able to work on designing new treatments based on KIFAP3. Treatments can now be directly designed to exploit the effect of this gene variation." (C)BBC
A gene linked to a type of motor neurone disease that runs in families has been found after a 10-year search. Along with a related gene reported last year, it opens up an unexplored area of research into the condition, investigators said. The finding will also help doctors screen and counsel families at risk of the disease, the US and UK team wrote in Science. Up to 10% of cases are inherited within families because of genetic mutations. Motor neurone disease (MND) involves the progressive wasting of the muscles, while usually leaving the mind unaffected. It affects some 5,000 people in the UK. The first MND gene - SOD1 - was found in 1993 and it has been a major focus of research. But then researchers found a protein called TDP-43 is deposited in the neurons of 90% of people with the condition. However, it was not apparent in animal models with the SOD1 mutation, suggesting that the first gene found is not linked with the major underlying biology of the disease. For the past decade the UK and US team have been looking for a gene believed to be located on chromosome 16. They eventually found a mutation in the FUS gene in one family with inherited MND - also known as amyotrophic lateral sclerosis. Further studies showed that 4% of all families had FUS mutations. The FUS gene is related to TDP-43, the gene for which was found by the same researchers last year. Professor Christopher Shaw, from the Institute of Psychiatry at Kings College London, said the FUS gene was a very important clue as to what causes motor neurons to degenerate. "It's very interesting, we really have wrung SOD1 out. We have looked at cells and mice endlessly, but the major pathways are not SOD pathways. The genetic pieces of the jigsaw puzzle are beginning to fit together, leading us in new and exciting directions of research." (C)BBC
Scientists have identified a molecule which could be key to understanding the cause of motor neurone disease (MND) and other neurodegenerative disorders. The Proceedings of the National Academy of Sciences study raise the hope of new treatments being developed. The London-based team showed the molecule, Wnt3, plays a key role in establishing connections between nerve cells and the muscles they control. These connections become progressively weaker in MND patients. Without properly-formed connections - or synapses - the muscle cannot receive the nerve signal that tells it to contract. This results in the muscle weakness that is typical of MND. However, scientists have not been clear how synapses are formed in normal circumstances and this has made it very difficult to pin down what goes wrong in MND. The researchers, from University College London and King's College London, identified Wnt3 as key to the process. It assists a second molecule, called Agrin, which co-ordinates construction of the connection - or synapse. Lead researcher Professor Patricia Salinas said: "The work we are publishing today puts an important piece of the puzzle in place and offers up a new possibility for developing drugs to treat MND and other neurodegenerative diseases. "If we can build up a thorough picture to show how synapses are normally formed between nerves and muscles we can start to look for any elements that aren't working properly in people with MND. This might also lead to strategies for nerve repair after an injury." (C)BBC
By Adam Brimelow British scientists are embarking on a major new trial to assess the impact of the mood stabiliser lithium as a treatment for motor neurone disease. They say the research is necessary because positive findings from a small-scale Italian study were "too dramatic to ignore". But they are urging patients with the disease not to take the treatment in advance of their results. They warn that some side-effects of lithium are potentially dangerous. There are about 5,000 people in the UK living with motor neurone disease (MND). At the moment there is no effective cure or treatment. It is often rapidly progressive and always fatal, usually within two to five years. The disease can affect any adult at any age, although it is more commonly found in men, and is most likely to strike between the ages of 50 and 70. Lithium, a naturally occuring element, has long been used as a treatment for some forms of depression, such as bipolar disorder. But recent laboratory tests and animal trials have suggested that it may also have a protective effect with MND. The recent trial of 16 people in Italy reported encouraging results. But the MND Association said the study was small and poorly designed, and that its findings should be treated with caution. The association's president, Professor Sir Colin Blakemore, said: "If you read the publication optimistically it might be taken to mean that lithium literally cures this disease. "But it's very important, against the background of patient hopes and expectations, to stand back and ask whether the trial was large enough to make the claims that it did." (C)BBC
Related chapters from BP7e: Chapter 11: Motor Control and Plasticity; Chapter 16: Psychopathology: Biological Basis of Behavior Disorders
Related chapters from MM:Chapter 5: The Sensorimotor System; Chapter 12: Psychopathology: The Biology of Behavioral Disorders
Link ID: 12201 - Posted: 11.03.2008
CHICAGO - A mutation in a single gene may raise one's risk of developing amyotrophic lateral sclerosis (ALS), also know as Lou Gehrig's disease, by as much as 30 percent, offering a potential new target for drug research, Dutch scientists said on Sunday. They said a variant in the DPP6 gene may give rise to ALS in people without a family susceptibility to the untreatable and fatal disease. Familial ALS, which accounts for 10 percent of all cases of the disease, has been linked with mutations in a number of other genes. Researchers have had less luck finding a gene associated with non-familial, sporadic ALS, which accounts for 90 percent of ALS cases. But researchers at the University Medical Center Utrecht said a SNP or single-letter change in the genetic code of the DPP6 gene is "consistently and strongly associated with susceptibility to amyotrophic lateral sclerosis in different populations of European ancestry." The DPP6 gene controls an enzyme found mostly in the brain that has been linked with spinal cord injury in rats. (c) Reuters 2007.
Scientists are hopeful that they have found a way to halt the progression of motor neurone disease (MND). A team at Bath University discovered a causal link between the gene involved in the formation of blood vessels and the development of some forms of MND. Mutant versions of the gene's product - angiogenin - are toxic to motor neurones, so blocking this process may stop the disease, they say. The latest UK work is published in the journal Human Molecular Genetics. There are about 5,000 people suffering with MND at any one time in the UK. The condition affects men more than women and one or two people in every 100,000 will be newly diagnosed with MND each year. In MND, over time, the cells responsible for transmitting the chemical messages that enable muscle movements become injured and subsequently die. Ultimately, the disease fatally interferes with those muscles involved in breathing. Last year, scientists discovered that some patients with MND have a mutated version of the human angiogenin gene. Since then, experts have been trying to find out what role angiogenin plays in the maintenance and development of motor neurones. Lead researcher Dr Vasanta Subramanian said: "We have found that mutated versions of this molecule are toxic to motor neurones and affect their ability to put out extensions called the axons. (C)BBC
Stem cells show potential for treating the debilitating nerve condition motor neurone disease, research suggests. A US team found injecting rats with stem cells delayed the onset of MND. Writing in the Transplantation, the researchers from Johns Hopkins Medical Institutions warned clinical use of stem cells was still a long way off. But they said their findings would help scientists to better understand how stem cells behaved when they were transplanted into the body. Motor neurone disease (MND) affects about 5,000 people in the UK. It is a progressive disorder caused by the break-down of the nerve cells, called motor neurones, which control the muscle activity. It is characterised by muscle-wasting, loss of mobility, and difficulties with speech, swallowing and breathing. To investigate whether stem cells - cells that can transform into any type of cell in the body - could help MND sufferers, scientists injected rats, bred to carry the most common form of MND, amyotrophic lateral sclerosis (AMS), with live human stem cells into their lower spines. They found that 70% of the transplanted cells developed into new nerve cells, and many of them had grown new endings connecting with other cells in the rats' spinal cords. The onset of the disease, marked by weight loss, was also delayed. It began on average at 59 days, in the rats injected with live stem cells, compared with 52 days for control rats that had been injected with dead, and therefore inactive, stem cells. They also discovered the rats with live stem cells grew weaker more slowly and lived longer than those that had received dead stem cell transplants. (C)BBC
Related chapters from BP7e: Chapter 11: Motor Control and Plasticity; Chapter 7: Life-Span Development of the Brain and Behavior
Related chapters from MM:Chapter 5: The Sensorimotor System; Chapter 13: Memory, Learning, and Development
Link ID: 9489 - Posted: 10.17.2006
EVANSTON, Ill. --- Two teams of researchers at Northwestern University have found a novel pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) at the molecular level. The neurologists and biochemists show how and why the mutated superoxide dismutase (SOD1) protein, which is associated with a familial form of ALS, becomes vulnerable and prone to aggregation and also provide evidence linking disease onset with the formation of intermolecular aggregates. The findings, which have implications for new therapeutics for the devastating disease, were published online this week in two related papers by the Proceedings of the National Academy of Sciences (PNAS). ALS is a progressive paralytic disorder caused by degeneration of motor neurons in the brain and spinal cord. The cause and development (pathogenesis) of the fatal disease are not known, and there is no effective treatment. Fifteen years ago, an international consortium led by Teepu Siddique, M.D., Les Turner ALS Foundation/Herbert C. Wenske Foundation Professor at Northwestern's Feinberg School of Medicine, mapped the first ALS gene to chromosome 21. Subsequently, they found that mutations in the SOD1 gene are responsible for 20 percent of familial (inherited) ALS cases. Siddique and his colleagues also made the first ALS transgenic mouse models. Although more than 100 types of a single mutation in the SOD1 gene have been identified and multiple lines of the mouse models developed, a key question remains to be answered: How does the genetic mutation alter this incredibly stable protein to make it so toxic that it kills motor neurons and causes neurodegenerative disease?
EVANSTON, Ill. --- French neurologist Jean-Martin Charcot first described amyotrophic lateral sclerosis (ALS) in 1869, but, nearly 140 years later, little is known about the cause of the devastating neurodegenerative disease, and there is no cure. What is known about Lou Gehrig's disease, as it is commonly called, is that misfolded and damaged proteins clump together in cells to form aggregates and motor neurons die. But scientists have long debated whether or not the protein aggregates actually kill the cells. Now a research team at Northwestern University, using mammalian neurons and live-cell time-lapse spectroscopy, has become the first to clearly link the presence of the ALS-associated mutant SOD1 protein aggregates with neuronal cell death. This evidence could help explain the disease process and eventually lead to new therapeutics. In the study, published this month in the Journal of Cell Biology, the scientists looked one at a time at neuronal cells expressing the mutant SOD1 protein and found that in cells where the protein accumulated and aggregates formed, 90 percent of the cells went on to die. (They died between six and 24 hours after aggregates were visually detected.) Cells that did not form aggregates did not die.
A UCSF study has found that a specific signaling link between neurons and muscles in the fruit fly is essential for keeping the insect's nervous system stable. The findings are relevant for ongoing research in identifying causes and developing treatments for neuromuscular neurodegenerative diseases in humans, such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, says study co-author Graeme Davis, PhD, associate professor and vice chair of the Department of Biochemistry and Biophysics at the University of California, San Francisco. "If we want to make new drugs to treat neurodegenerative disease, then we have to identify new drug targets, and our study findings present that potential," he says. "This study is a significant step forward because we have shown that a signaling system composed of several genes is important for keeping the nervous system stable." The findings are reported in the September issue of the journal Neuron. The nervous system is a complex pattern of connections that exists for the entire life of the organism, and understanding how the myriad patterns and pathways of these connections are maintained for long periods of time presents an ongoing challenge to scientists, says Davis.
MADISON -- Unveiling a delivery method that may one day help surgeons treat the deadly neurodegenerative disease amyotrophic lateral sclerosis (ALS), researchers at the University of Wisconsin-Madison have inserted engineered human stem cells into the spinal cords of ALS-afflicted rats. Reporting their work today (April 19) in the journal Human Gene Therapy, the scientists directed certain types of neural stem cells to secrete a neuron-protecting protein before injecting them into the rat spinal cord where motor neurons reside. Motor neurons dictate muscle movement by relaying messages from the spinal cord and brain to the rest of the body. ALS causes the neurons to progressively decay and die. Notably, the UW-Madison stem cell researchers did not work with human embryonic stem cells, blank-slate cells that arise during the earliest stages of development and can develop into any of the 220 tissue and cell types in humans. Scientists have long regarded these cells as a crucial ingredient in the quest to cure spinal injuries and neurodegenerative disease. Rather, the scientists worked with more specialized neural stem cells -- known as neural progenitor cells -- that arise from primitive stem cells during the first few weeks of human brain development. Unlike embryonic stem cells, they can only develop into neural tissue and they are incapable of living forever, as embryonic stem cells can.
By BARRON H. LERNER, M.D. When my patient Jackie, who had incurable lung cancer, came to my office, she would regale me with her latest physical accomplishments. "I'm doing great, doctor, right?" she would ask. As I answered this and other questions from her, I struggled to balance the reality of Jackie's prognosis with a hopeful outlook. Now a new book describes another doctor who did the same for his patient, who had a fatal neurological disease. That patient was Lou Gehrig. The Hippocratic Oath and other ethical codes that guided the medical profession for centuries generally omitted the notion of truth-telling. In fact, one of Hippocrates's injunctions, to keep the sick from harm and injustice, encouraged the opposite behavior, deception. Serious illnesses, after all, were bad news. While doctors could give pain medications and other palliatives to patients with widespread cancer or tuberculosis, no cures existed. Faced with such situations, physicians often actively misled their patients, using euphemisms like "tumor" or "growth" when describing cancer. These doctors believed that the unvarnished truth would not only be emotionally hurtful, but it would lead patients to give up and thus die sooner. Copyright 2005 The New York Times Company
Scientists at the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland have used RNA interference in transgenic mice to silence a mutated gene that causes inherited cases of amytrophic lateral sclerosis (ALS), substantially delaying both the onset and the progression rate of the fatal motor neuron disease. Their results will be published in the April issue of Nature Medicine, and in the journal's advanced online publication March 13. In addition to silencing the mutated gene that causes ALS, the EPFL researchers were able to simultaneously deliver a normal version of the gene to motor neuron cells using a single delivery mechanism. "This is the first proof of principle in the human form of a disease of the nervous system in which you can silence the gene and at the same time produce another normal form of the protein," notes Patrick Aebischer, EPFL President and a co-author of the study. ALS is a progressive neurological disease that attacks the motor neurons controlling muscles. Although its victims retain all their mental faculties, they experience gradual paralysis and eventually lose all motor function, becoming unable to speak, swallow or breathe. Known also as Lou Gehrig's disease, from the baseball player who succumbed to it, this harrowing disease has no cure and its pathogenesis is not very well understood.
By NICHOLAS BAKALAR Why soccer would be a risk for amyotrophic lateral sclerosis is a mystery. But a new study has found that Italian professional soccer players get the disease at a rate nearly six times as great as the general population. The study, led by Dr. Adriano Chiň, a professor in the department of neuroscience at the University of Turin, was inspired by the work of an Italian prosecutor, Raffaele Guariniello, who was investigating soccer players' use of illegal drugs. As part of his inquiry, he ordered a report on the causes of death among 24,000 men who played professional or semiprofessional soccer in Italy from 1960 to 1996. His finding - that Italian players died of A.L.S. at a rate almost 12 times as great as normal - puzzled researchers, who decided to undertake a much more rigorous study. A.L.S., often called Lou Gehrig's disease, is an incurable and invariably fatal degenerative disease of the nervous system. Although there have been many suggestions about the possible risks for the illness, including participation in sports, no clear-cut evidence has been found for any risk factors except age and sex. (A.L.S. tends to strike around age 60, and a vast majority of patients are men.) Copyright 2005 The New York Times Company
MADISON - After years of trial and error, scientists have coaxed human embryonic stem cells to become spinal motor neurons, critical nervous system pathways that relay messages from the brain to the rest of the body. The new findings, reported online today (Jan. 30, 2005) in the journal Nature Biotechnology by scientists from the University of Wisconsin-Madison, are important because they provide critical guideposts for scientists trying to repair damaged or diseased nervous systems. Motor neurons transmit messages from the brain and spinal cord, dictating almost every movement in the body from the wiggling of a toe to the rolling of an eyeball. The new development could one day help victims of spinal-cord injuries, or pave the way for novel treatments of degenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. With healthy cells grown in the lab, scientists could, in theory, replace dying motor neurons to restore function and alleviate the symptoms of disease or injury. Much sooner in the future, the advance will allow researchers to create motor neuron modeling systems to screen new drugs, says study leader Su-Chun Zhang, an assistant professor of anatomy and neurology in the Stem Cell Research Program at the Waisman Center at UW-Madison.
ALS is an incurable, paralyzing neurodegenerative disorder that strikes 5 persons in every 100,000. The disease commonly affects healthy people in the most active period of their lives - without warning or previous family history. Researchers from VIB (the Flanders Interuniversity Institute for Biotechnology), under the direction of Prof. Peter Carmeliet (Catholic University of Leuven), have previously shown the importance of the VEGF protein in this disease. Now, new research from this group shows that rats with a severe form of ALS live longer following the administration of the VEGF protein as a remedy. These results open up new possibilities for the use of VEGF in the treatment of ALS. An incurable disease of the muscles Amyotrophic Lateral Sclerosis (ALS) can strike anyone. The Chinese leader Mao Tse Tung, Russian composer Dimitri Sjostakowitz, the legendary New York Yankee baseball player Lou Gehrig, and astro-physicist Stephen Hawkins have all been afflicted with ALS. In addition, an unusually large number of Italian professional soccer players, airline pilots, and soldiers from the Golf War have been stricken by this fatal disease. About half of them have died within three years - some even in the first year - and usually as a consequence of asphyxiation, while still 'in full possession of their faculties'. In ALS, the patient's nerve bundles that extend to the muscles deteriorate. This causes the patient to lose control over his/her muscles, growing progressively paralyzed - but remaining (disconcertingly) fully alert mentally. The originating mechanism of this deadly disease of deterioration - which has an enormous medico-social impact - remains obscure. At present, the disease is totally untreatable - causing many ALS patients to choose euthanasia, a very controversial solution. However, previous genetic research by Peter Carmeliet and his team at the Catholic University of Leuven has led to the surprising discovery that the vascular endothelial growth factor (VEGF) plays a major role in this disease.
By JOHN SCHWARTZ and JAMES ESTRIN Dr. Jules Lodish welcomes visitors to the downstairs bedroom of his Bethesda, Md., home with a robotic greeting that bursts from his computer's speaker. Ten years of living with amyotrophic lateral sclerosis, or A.L.S., a progressive, paralyzing disease, have stilled nearly every muscle; he types with twitches of his cheek, detected by a sensor clipped to his glasses. But ask him how he feels about his life, and Dr. Lodish, his eyes expressing the intensity denied to his body, responds: "I still look forward to every day." A.L.S., or Lou Gehrig's disease, is often described as a kind of living death in which the body goes flaccid while the mind remains intact and acutely aware. The prospect of being trapped in an inert body and being totally dependent on others drives many sufferers to suicide. When Attorney General John Ashcroft attacked an Oregon law allowing doctor-assisted suicide in 2001 - a case that is still working its ways through the legal system - patients with the disease were among those who supported the law in court. But while the legal case and much of the national attention has focused on the issue of the right to die, less is known about those patients who want to live, and, like Dr. Lodish, will go to extraordinary lengths to do so. Copyright 2004 The New York Times Company
Human primitive spinal cord cells delayed symptoms and paralysis by a week when implanted in the spinal cord of rats destined to develop amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, researchers from Johns Hopkins report. The human neuronal stem cells were obtained from embryos by scientists at biotech company Neurostem Inc., transferred to Hopkins and implanted into the lower part of the rats' spinal cords about a month before the animals usually develop muscle control problems characteristic of ALS. The treatment delayed the animals' death by 11 days. Research associate Leyan Xu, Ph.D., is scheduled to present the results Oct. 23 at the annual meeting of the Society for Neuroscience in San Diego. "This rat model of ALS progresses very rapidly -- within two or three weeks of symptoms appearing, the rats have to be euthanized -- so the delay we saw is quite significant," says the study's senior author, Vassilis Koliatsos, M.D., associate professor of pathology, neurology, neuroscience and psychiatry and behavioral sciences at Hopkins. "Our study is proof of principle, that neuronal stem cells do have potential in conditions caused by separation within the nervous system, whether by disease or injury."
The selective killing of spinal cord neurons in amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, occurs when tiny cellular components called mitochondria actively recruit a mutant disease-causing protein into specific neuron cells, according to new research by University of California, San Diego (UCSD) School of Medicine investigators. Published in the July 8, 2004 issue of the journal Neuron, the findings identify mitochondria as the focus of ALS toxicity and provide the first explanation of how a mutant protein called SOD1 that occurs in all cells in the body is damaging only to specific neuron cells. The result is ALS, a progressive degeneration of motor nerve cells in the spinal cord that leads to wasted muscles and premature death in middle-aged adults. Found in all cells, mitochondria provide cellular energy in their role as the body's power generators. In addition, mitochondria are intricately involved in a process called apoptosis, or programmed cell death, which is the body's normal method of disposing of damaged, unwanted or unneeded cells. "We believe that when the mutant SOD1 binds to mitochondria, it affects the ability of these components to generate cell energy," said the study's senior author, Don Cleveland, Ph.D., a UCSD professor of medicine, neurosciences, and cellular and molecular medicine, and a faculty member of the Ludwig Institute for Cancer Research.