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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.
ALS is an incurable paralysing muscle disorder affecting five in every one hundred thousand people. The disease mainly strikes healthy people in the most active period of their life, without any warning or family history. Researchers from VIB (the Flanders Interuniversity Institute for Biotechnology), lead by Prof. Peter Carmeliet (K.U.Leuven) already indicated the importance of the VEGF protein in this illness, on the basis of genetic studies. In cooperation with Oxford BioMedica, an Oxford-based biotech company, a new study of the VIB researchers indicates that gene therapy with VEGF appears to be one of the most promising therapies. By administering the gene that produces VEGF in the nerve trajectory of ALS mice, the researchers were able to slow down the development of the illness and increase their life expectancy by 30% - the largest therapeutic effect ever achieved for ALS. ALS can affect anyone. Chinese leader Mao Tse Tung, Russian composer Dimitri Sjostakowitz, legendary Yankee baseball player Lou Gehrig and astrophysicist Stephen Hawkins were all affected by ALS. A large number of Italian top football players, pilots and soldiers in the Gulf War were also affected by this fatal disease. Around half of them die within three years, some even within a year, mostly in full possession of their faculties as a result of asphyxiation.
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: 5542 - Posted: 05.28.2004
Scientists may have developed a gene therapy treatment for the most common form of motor neurone disease (MND). In lab tests on mice the therapy slowed onset and progression of Amyotrophic Lateral Sclerosis (ALS). It also extended life expectancy by 30%. Writing in the journal Nature, the research team at biopharmaceutical firm Oxford BioMedica stressed the work is at an early stage. MND affects about 5,000 people in the UK and there are 1,000 new cases a year. The disease is caused by the death of cells - called motor neurones - that control movement in the brain and spinal cord. There is currently no known cure. ALS is a form of the disease which affects adults, leading to paralysis and death within five years for most patients. The new treatment - called MoNuDin - essentially consists of a gene which triggers production of a chemical called a vascular endothelial growth factor (VEGF). The gene is injected into the muscles, but stimulates VEGF production in the nerve cells of the spine. (C)BBC
The scientists who cloned Dolly the sheep are applying for a licence to clone human embryos. Professor Ian Wilmut, of the Roslin Institute in Edinburgh, wants to use cloned human embryos to study motor neurone disease (MND). His application to the Human Fertilisation and Embryology Authority is expected to provoke criticism that testing human embryos is immoral. Therapeutic cloning for research has been legal in the UK since 2001. It is designed purely for research. Professor Wilmut has stressed that his team has no intention of producing cloned babies, and said the embryos would be destroyed after experimentation. He told the BBC: "Because at this early stage the embryo does not have that key human characteristic of being aware to me it would be immoral not to take this opportunity to study diseases." Until recently, Professor Wilmut had said he would not work with human embryos. (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: 5333 - Posted: 04.21.2004
Researchers have discovered a genetic mutation associated with an inherited form of motor neuron disease in which symptoms first appear in childhood or young adulthood. The finding is slated for publication in the American Journal of Human Genetics. In studying families affected by the disease, researchers detected a mutation in the Senataxin gene. Although this gene's exact function is unknown, scientists think the normal Senataxin gene may play a role in how cells rid themselves of faulty genetic messages during RNA processing, according to Dr. Craig Bennett, University of Washington (UW) research assistant professor of pediatrics, Division of Genetics and Developmental Medicine. The mutation may make it difficult for motor neuron cells to clear out mistakes made during encoding of DNA, and thereby contribute to the degeneration of these nerve cells. The disease studied is a rare type of amyotrophic lateral sclerosis (ALS). Patients with this type of ALS have mild symptoms, a slow progression of muscle weakness, a normal life span, and relatives with the same disorder. In contrast, most ALS disorders appear in middle age or later life and cause paralysis and death within a few years. Only 10 percent of ALS disorders run in families; the rest appear sporadically. ALS claimed the life of baseball star Lou Gehrig, and is often called Lou Gehrig's disease.
By STEPHEN S. HALL AMONG many exquisitely rendered moments in Jonathan Weiner's ''His Brother's Keeper: A Story From the Edge of Medicine,'' a simple daily act of fine motor skill early on quietly explodes into a moment of heartbreaking significance, when a young carpenter named Stephen Heywood inserts a key one morning into the front door of a cottage he has been lovingly restoring in Palo Alto, Calif. A self-described slacker, a brown dwarf of a star in an otherwise brilliant constellation of familial ambition, Stephen has struggled to find his niche, professionally and perhaps emotionally, in a family of overachievers based in Newton, Mass. His mother, Peggy, is a retired psychotherapist; his father, John, is director of an engineering lab at the Massachusetts Institute of Technology; his younger brother, Ben, is trying to make it in Hollywood as a producer; and his other brother, Jamie, two years older, is not just an M.I.T.-educated mechanical engineer of uncommon vision and intuition, but a larger-than-life personality who has yet to meet a challenge he cannot overcome. The family's greatest challenge begins to announce itself that morning in December 1997, when Stephen discovers that try as he might, he is unable to turn the key in the lock with his right hand. It is an early sign that he is suffering from amyotrophic lateral sclerosis (A.L.S.), often called Lou Gehrig's disease. Copyright 2004 The New York Times Company
Bat specimens dating back more than 50 years may help scientists understand high rates of a killer disease on a Pacific island. Guam is known for incredibly high rates of a degenerative disease which has some of the hallmarks of motor neuron, Parkinson's and dementia, but cannot be firmly identified as any of them. Among the Chamorro people on the island, rates of the mysterious condition run at between 50 and 100 times the "normal" rate of motor neuron disease found in other communities. Many theories have been put forward as to the cause of the disease, but the mystery has yet to be solved. In recent years, some researchers have suggested that islanders habit of catching and eating a type of bat called a flying fox may be to blame. It is suggested that the flying foxes feed on seed containing a chemical highly toxic to human brain cells. (C) BBC
Cathy Burgess, a Nottinghamshire woman with motor neurone disease (ALS), wanted more people to know about the illness. She spoke to BBC News about the disease a few weeks before her death. "It was like someone had crept up on me and an icy hand grabbed my heart while I wasn't looking and stole my future." Cathy, who was 48, only discovered she had motor neurone disease two years ago. "I promised myself to learn a new skill every year and I did - skiing, sailing, ballroom dancing, scuba diving and sky-diving. "One of the things I always say is that my family and support network are my parachute." (C) BBC
3-dimensional pictures of ALS mutant proteins support two major theories about how the disease is caused A new study reveals for the first time how gene mutations lead to the inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. The study suggests that the two most prominent theories of how familial ALS (FALS) and other related diseases develop are both right in part. "No one has ever demonstrated at the molecular level how ALS mutations might lead to disease," says study author John Hart, Ph.D., director of the University of Texas Health Science Center X-ray Crystallographic Core Laboratory in San Antonio. "Using a technique commonly used in structural biology, we could see the intimate details of how toxic familial ALS proteins interact. And we found out that the proteins are interacting in a way they shouldn't be." The study was funded by the National Institute of Neurological Disorders and Stroke and appears in the June 2003 issue of Nature Structural Biology. ALS is a progressive, fatal neurological disease that usually strikes in mid-life. It causes muscle weakness, leads to paralysis, and usually ends in death within 2 to 5 years of diagnosis. Affecting as many as 20,000 Americans, ALS occurs when specific nerve cells in the brain and spinal cord that control voluntary movement gradually degenerate.