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By Laurie McGinley Independent advisers to the Food and Drug Administration on Wednesday voted 7 to 2 to recommend approval of an experimental ALS drug with strong support from patients and advocates, making it likely the hotly debated treatment will be cleared by the agency within weeks. The vote was a stunning turnaround from late March when the panel voted 6 to 4 to recommend against FDA approval. At that meeting, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee concluded the evidence from a single clinical trial — with just 137 patients and some follow-up data — was not sufficient to show the drug, called AMX0035, slowed a degenerative disease that usually kills people within three to five years. But on Wednesday, after hours of discussion, several advisers said that additional analyses submitted by the drug’s manufacturer, Cambridge-based Amylyx, bolstered the case for approval, even though uncertainties remain. Advisers were also affected by the disease’s severity and the lack of effective treatments. A vow by a top Amylyx official to pull the drug from the market if a larger study, with 600 patients, fails to show effectiveness was also a factor in the vote. The FDA, which usually follows the recommendation of its outside advisers but is not required to, is expected to decide whether to approve the drug by Sept. 29. The improved fortunes of the medicine came despite criticism from FDA staff as recently as last week about the treatment’s effectiveness, the conduct of its clinical trial and the researchers’ interpretation of the data. But the medicine is considered safe, and the agency has been under intense pressure from ALS patients and physicians who say the treatment holds promise for a fatal disease that typically causes rapid deterioration and death.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 28467 - Posted: 09.10.2022

Researchers have published two papers describing how they identified a potential new pathway for treating a sporadic form of amyotrophic lateral sclerosis (ALS). The studies were published as part of a cooperative research agreement between the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, and the Switzerland-based biotechnology company GeNeuro Inc. One unusual side effect of hundreds of thousands of years of evolution is that the human genome now contains DNA sequences from ancient retroviruses—referred to as human endogenous retroviruses (HERVs). Though most remain dormant, reactivation of HERVs have been implicated in several neurodegenerative diseases, including ALS. The first of these papers shows that a specific HERV produces a protein that can be found in the cerebrospinal fluid (CSF) of people with ALS. This protein, called HERV-K ENV, is toxic when added to neurons grown in laboratory dishes. In addition, a special kind of mouse genetically designed to create HERV-K ENV develops symptoms very similar to ALS. Adding the CSF from people with ALS to lab-grown neurons resulted in damage to the cells. When a synthetic antibody designed specifically to recognize HERV-K ENV was added as well to those neurons, the toxic effects were reduced. These findings together suggest that the improper activation of the HERV-K ENV gene could be the cause of the symptoms seen in certain cases of sporadic ALS. The discovery that a synthetic antibody to HERV-K ENV could be protective led the researchers to look at whether the immune system of people with ALS produced any antibodies, as well. In the second paper, the authors show that indeed higher levels of antibodies against HERV-K ENV were seen in the blood of a group of people with ALS as compared to healthy donors. The pattern of antibodies against this viral protein was also more complex in persons with ALS. In addition, there was also a correlation between higher antibody levels against HERV-K ENV and longer overall survival.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 28455 - Posted: 08.31.2022

By Pam Belluck An experimental therapy for A.L.S., the paralyzing and fatal neurological disorder, has been approved in Canada, adding a new treatment option for a disease for which there are few effective therapies. The approval, the first in the world for the treatment — AMX0035, to be marketed in Canada as Albrioza — comes with the condition that the drug company later provide better evidence that the treatment works. It is likely to be of major interest to patients with A.L.S. (amyotrophic lateral sclerosis) in the United States, where the same therapy is being evaluated by the Food and Drug Administration, which has raised questions about the treatment’s effectiveness. An F.D.A. review earlier this year found the treatment to be safe, but said there was not enough evidence that it was effective either in helping patients live longer or slowing the rate at which they lose functions like muscle control, speaking or breathing without assistance. A committee of independent advisers to the F.D.A. voted by a narrow margin in March that the therapy was not ready for approval. The F.D.A. had been scheduled to issue a final decision this month, but recently extended the deadline to Sept. 29, saying it needed more time to review additional analyses of data submitted by the company. In the meantime, Calaneet Balas, president and chief executive of the A.L.S. Association, one of several patient advocacy organizations pressing for F.D.A. approval, said, “We expect that Americans living with A.L.S. will try to access Albrioza in Canada, just as we have heard reports of people trying to buy the ingredients on Amazon.” © 2022 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 28369 - Posted: 06.14.2022

Linda Geddes A completely locked-in patient is able to type out words and short sentences to his family, including what he would like to eat, after being implanted with a device that enables him to control a keyboard with his mind. The findings, published in Nature Communications, overturn previous assumptions about the communicative abilities of people who have lost all voluntary muscle control, including movement of the eyes or mouth, as well as giving a unique insight into what it’s like to be in a “locked in” state. Locked-in syndrome – also known as pseudocoma - is a rare condition, where people are conscious and can see, hear, and smell, but are unable to move or speak due to complete paralysis of their voluntary muscles, eg as a result of the progressive neurodegenerative disease amyotrophic lateral sclerosis (ALS). Advertisement Some can communicate by blinking or moving their eyes, but those with completely locked-in syndrome (CLIS) cannot even control their eye muscles. In 2017, doctors at the University of Tübingen in Germany enabled three patients with CLIS to answer “yes” or “no” to questions by detecting telltale patterns in their brain activity, using a technology called functional near-infrared spectroscopy (fNIRS). The advance generated widespread media coverage, and prompted the parents of the current patient, who was diagnosed with ALS in 2015, to write to the medical team, saying he was losing the ability to communicate with his eye movements, and could they help. The problem with using fNIRS to help CLIS patients to communicate is that it is relatively slow, and only gives the correct answer 70% of the time, meaning questions have to be repeated to get a reliable answer. “It was always our goal to enable a patient in a completely locked down state to spell out words, but with a classification accuracy of 70%, it is almost impossible to enable free spelling,” said Dr Ujwal Chaudhary, a biomedical engineer and managing director of ALS Voice gGmbH in Mössingen, Germany, who co-led the research. © 2022 Guardian News & Media Limited

Related chapters from BN: Chapter 2: Functional Neuroanatomy: The Cells and Structure of the Nervous System; Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 2: Neurophysiology: The Generation, Transmission, and Integration of Neural Signals; Chapter 5: The Sensorimotor System
Link ID: 28250 - Posted: 03.23.2022

Christopher McDermott, MBChB, FRCP, PhD Early in my clinical practice, my team and I subscribed to the traditional view of ALS: the disease was either familial or sporadic. People with “familial” ALS had some family history of ALS (and therefore a possible genetic component), while people with “sporadic” disease did not have a family history.1 But that view began to change with the discovery that mutations (or changes) in a gene called C9orf72 could play a role in both the sporadic and familial types of ALS. Over time, we learned that this one mutation accounted for approximately 40% of familial ALS cases. Even more surprising: it accounted for close to 10% of cases in people with no family history of ALS—people previously believed to have the sporadic form of the disease. As this story unfolded, we began to question our old assumptions about familial and sporadic ALS, and we realized that just asking our patients about their family history wasn’t enough. C9orf72 has been associated with other neurologic diseases as well, so now, I and other ALS specialists understood that someone with a family history of related conditions might also have a genetic cause for their ALS. At the same time, other genetic mutations were being found in people with no family history of the disease and whose ALS had seemingly appeared out of nowhere.1 It was becoming clear that some people with what we often referred to as sporadic ALS could actually have a genetic component to their disease.1 My own research supported this belief. The Sheffield Institute for Translational Neuroscience, where we help develop and study new therapies for neuromuscular diseases, had an extensive biobank of samples from people with ALS. As new genetic mutations were discovered, our researchers tested these samples and found that many people who we thought had sporadic ALS in fact had one or more genetic mutations. © 2013-2021 All rights reserved.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27885 - Posted: 07.03.2021

Ian Sample Science editor Regular strenuous exercise raises the risk of developing motor neurone disease (MND) in people who are genetically predisposed to the condition, researchers say. Scientists at the University of Sheffield found a causal relationship between high intensity physical activity and the disorder among those already susceptible to the disease. They believe the work marks a major step towards understanding the link between intense exercise, which may contribute to motor neurone injury in certain people, and the neurodegenerative disease, which affects about 5,000 individuals in the UK. “We have suspected for some time that exercise was a risk factor for MND, but until now this link was considered controversial,” said Dr Johnathan Cooper-Knoc, a neurologist at Sheffield. “This study confirms that in some people, frequent strenuous exercise leads to an increase in the risk of MND.” The life-time risk of developing MND is about 1 in 400, but previous studies have suggested it is six times greater in professional football players compared with the general population. A number of high-profile British sportsmen have shared their experience with MND in recent years, including rugby league’s Rob Burrow, rugby union’s Doddie Weir and the the footballer Stephen Darby. The Sheffield researchers emphasise that the vast majority of people who undertake vigorous exercise do not develop MND, and that their next step is to develop tests that identify people most at risk. © 2021 Guardian News & Media Limited

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27848 - Posted: 06.11.2021

Michelle Andrews Once the rules for implementing it are worked out, a bill signed into federal law in December will eliminate the required five-month waiting period for diagnosed ALS patients to begin disability benefits, enabling quicker Medicare coverage as well. LumiNola/Getty Images Anita Baron first noticed something was wrong in August 2018, when she began to drool. Her dentist chalked it up to a problem with her jaw. Then her speech became slurred. She managed to keep her company going — it offers financing to small businesses — but working became increasingly difficult for her as her speech worsened. Finally, nine months, four neurologists and countless tests later, Baron, now 66, got a diagnosis: amyotrophic lateral sclerosis. ALS, often called Lou Gehrig's disease after the New York Yankees first baseman who died of the disease in 1941, destroys motor neurons, causing people to lose control of their limbs, their speech and, ultimately, their ability to breathe. It's usually fatal in two to five years, though about 10% of people survive ten years or more. People with ALS often must quit their jobs — and sometimes their spouses do, too, to provide care — leaving families in financial distress. A decade-long campaign by advocates highlighting this predicament notched a victory last month when Congress passed a bill opening key support programs earlier for ALS patients. © 2021 npr

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27652 - Posted: 01.20.2021

A study led by researchers at the National Institutes of Health has made a surprising connection between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two disorders of the nervous system, and the genetic mutation normally understood to cause Huntington’s disease. This large, international project, which included a collaboration between the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), opens a potentially new avenue for diagnosing and treating some individuals with FTD or ALS. Several neurological disorders have been linked to “repeat expansions,” a type of mutation that results in abnormal repetition of certain DNA building blocks. For example, Huntington’s disease occurs when a sequence of three DNA building blocks that make up the gene for a protein called huntingtin repeats many more times than normal. These repeats can be used to predict whether someone will develop the illness and even when their symptoms are likely to appear, because the more repeats in the gene, the earlier the onset of disease. “It has been recognized for some time that repeat expansion mutations can give rise to neurological disorders,” said Sonja Scholz, M.D., Ph.D., investigator, NINDS Intramural Research Program. “But screening for these mutations throughout the entire genome has traditionally been cost-prohibitive and technically challenging.” Taking advantage of technology available at NIH, the researchers screened the entire genomes from large cohorts of FTD/ALS patients and compared them to those of age-matched healthy individuals. While several patients had a well-established genetic marker for FTD/ALS, a small subset surprisingly had the same huntingtin mutation normally associated with Huntington’s disease. Remarkably, these individuals did not show the classical symptoms of Huntington’s but rather those of ALS or FTD.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27604 - Posted: 12.05.2020

By Concepción de León Pat Quinn, who helped raise $220 million to fight amyotrophic lateral sclerosis, or A.L.S., by promoting the Ice Bucket Challenge in 2014, died on Sunday, seven years after he learned he had the disease. He was 37. His death, at St. John’s Riverside Hospital in Yonkers, N.Y., was confirmed by the A.L.S. Association and in a post on his official Facebook page. Mr. Quinn did not create the challenge, in which people dumped buckets of ice water on their heads while pledging to donate money to fight A.L.S. But he and his friend Pete Frates, who also had A.L.S., are credited with amplifying it and helping to make it a sensation in the summer and fall of 2014, raising tens of millions of dollars for research and, perhaps nearly as important, wider awareness of the disease. “Pat changed the trajectory of the fight against A.L.S. forever,” Calaneet Balas, the president and chief executive of the A.L.S. Association, said in a statement on Sunday. “He inspired millions to get involved and care about people who are living with A.L.S.” A.L.S., also called Lou Gehrig’s disease, is a progressive neurodegenerative disorder that attacks the nerve cells that control voluntary muscle movements and leads to full paralysis. People with the disease typically live three to five years from the time of diagnosis, according to the National Institute of Neurological Disorders and Stroke. Shortly after Mr. Quinn learned he had A.L.S. in 2013, he created Quinn for the Win, a Facebook group, to raise awareness of the disease and to raise money to fight for a cure. Mr. Frates created his own page, Team Frate Train, with the same goal. In July 2014, Mr. Quinn and Mr. Frates saw another A.L.S. patient, Anthony Senerchia, do the Ice Bucket Challenge online. They created their own ice-bucket videos and shared the challenge with their followers. (Mr. Frates died last year at age 34.) In Her Words: Where women rule the headlines. From there, the campaign spread wildly, with Lady Gaga, Oprah Winfrey, LeBron James and scores of other celebrities participating and donating to the cause. The challenge raised $115 million for the A.L.S. Association and $220 million around the world for A.L.S. research in the span of just six weeks, the A.L.S. Association said. © 2020 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27596 - Posted: 11.30.2020

By Sam Roberts Chris Pendergast, a Long Island teacher who defied the odds by surviving 27 years with Lou Gehrig’s disease, leading marathon “rides for life” for hundreds of miles from his motorized wheelchair to publicize the plight of fellow patients and raise $10 million for research, died on Oct. 14 at his home in Miller Place, N.Y. He was 71. His wife, Christine Pendergast, said the cause was complications of amyotrophic lateral sclerosis, the medical term for the disease that ended the career of Gehrig, the Yankee first baseman who, after playing in 2,130 consecutive games, proclaimed himself “the luckiest man on the face of the earth.” Gehrig died two years later, shortly before his 38th birthday. Mr. Pendergast was a 44-year-old teacher of gifted students at Dickinson Avenue elementary school in East Northport, on Long Island, when his eyes and hands began twitching and he started getting muscle spasms. On Oct. 13, 1993, he received the diagnosis: He had A.L.S., a degenerative disease, which diminishes muscle function and eventually the ability to breathe. The prognosis: He had three to five years to live. But Mr. Pendergast proved to be indomitable. He recast himself as the disease’s self-described squeaky wheel — “Since there’s no surviving constituency for A.L.S., there’s no squeaky wheel,” he told The New York Times in 2008. He founded the A.L.S. Ride for Life in 1997. The following year it mounted a 350-mile, two-week cavalcade from Yankee Stadium in the Bronx to Washington, with Mr. Pendergast leading it from his wheelchair. Subsequent annual rides went from Long Island’s East End to Manhattan with a small group of fellow patients. “We are dying men riding for life,” he told The Baltimore Sun in 2000. © 2020 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27557 - Posted: 10.31.2020

By Pam Belluck A potential therapy for amyotrophic lateral sclerosis, a fatal neurological disorder, may allow patients to live several months longer than they otherwise would have, according to a study published Friday. The two-drug combination, dreamed up by two college students, is one of several potential treatments raising the hopes of patients with A.L.S., also known as Lou Gehrig’s disease. The paralytic condition steals people’s ability to walk, speak, eat and ultimately breathe, typically causing death within two to five years. There are only two approved A.L.S. medications, neither tremendously effective. But advocacy efforts by patients and organizations, along with the Ice Bucket Challenge, a highly successful fundraising campaign, have galvanized research into more than 20 therapies that are currently in clinical trials. The two-drug combination, called AMX0035, was conceived seven years ago by Joshua Cohen and Justin Klee, then a junior and senior at Brown University, with the goal of preventing the destruction of neurons that occurs in many brain disorders. It is a combination of an existing supplement and a medication for a pediatric urea disorder. Last month, a study of 137 patients reported that AMX0035 slowed progression of A.L.S. paralysis by about 25 percent more than a placebo. Measuring patients using a scale of physical function, researchers found that those receiving a placebo declined in 18 weeks to a level that patients receiving the treatment didn’t reach until 24 weeks, according to the study’s principal investigator, Dr. Sabrina Paganoni. But because that trial was conducted for only 24 weeks, it left unanswered a crucial question of whether the treatment extended survival for the patients receiving the therapy. After that study ended, 98 of the participants, who had not been told whether they had received placebo or therapy, were given the option of taking the therapy for up to 30 months, a format called an open-label extension study. © 2020 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27533 - Posted: 10.19.2020

By Pam Belluck Seven years ago, Joshua Cohen, then a junior at Brown University majoring in biomedical engineering, was captivated by the question of why people develop brain disorders. “How does a neuron die?” he wondered. After poring over scientific studies, he sketched out his ideas for a way to treat them. “I was sitting in my dorm room and I had kind of written out the research on these crazy-looking diagrams,” he recalled. A study published on Wednesday in the New England Journal of Medicine reported that the experimental treatment he and another Brown student, Justin Klee, conceived might hold promise for slowing progression of amyotrophic lateral sclerosis, the ruthless disease that robs people of their ability to move, speak, eat and ultimately breathe. More than 50 clinical trials over 25 years have failed to find effective treatments for A.L.S., also called Lou Gehrig’s disease, which often causes death within two to five years. But now, scientific advances and an influx of funding are driving clinical trials for many potential therapies, generating hope and intense discussion among patients, doctors and researchers. The new study reported that a two-drug combination slowed progression of A.L.S. paralysis by about six weeks over about six months, approximately 25 percent more than a placebo. On average, patients on a placebo declined in 18 weeks to a level that patients receiving the treatment didn’t reach until 24 weeks, said the principal investigator, Dr. Sabrina Paganoni, a neuromuscular medicine specialist at Massachusetts General Hospital’s Healey & AMG Center for A.L.S. “It’s such a terrible disease and as you can imagine, for the folks who have it or the family members, it’s just desperation that something’s going to work,” said Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, who wasn’t involved in the new study. “Any kind of slowing of progression for a patient with A.L.S. might be valuable even though it’s not a big effect.” © 2020 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27455 - Posted: 09.05.2020

Laura P.W. Ranum An FDA-approved diabetes drug shows early signs of promise against the most common genetic form of amyotrophic lateral sclerosis, a devastating neurological condition that causes paralysis. ALS is a progressive disease that affects neurons in the brain and spinal cord. Motor neurons transmit signals from our brain to our muscles and allow us to move. ALS causes these motor neurons to die, resulting in the loss of a patient’s ability to speak, eat, move and breathe. Notable ALS patients include New York Yankees baseball star Lou Gehrig (the disease is often called Lou Gehrig’s disease), physicist Stephen Hawking and New Orleans Saints football star Steve Gleason. There are currently more than 30,000 cases of ALS in the United States, and life expectancy after diagnosis is typically 2 to 5 years. There is currently no cure for ALS. I am a scientist who studies neurological diseases that run in families, and I have been working hard to find a treatment to stop ALS. Our team has made a discovery, detailed in a scientific study, that paves the way for further research for improving disease in a genetic type of ALS caused by a mutation in a gene with the unwieldy name chromosome 9 open reading frame 72 (C9orf72), based on its location on chromosome 9. In addition to ALS, mutations in this gene can also cause frontotemporal dementia, which can cause apathy, loss of emotional control and cognitive decline. Some patients with the C9orf72 mutation develop ALS, others develop frontotemporal dementia and some develop both. Together, these diseases are referred to here as C9-ALS/FTD. I have been focusing on C9-ALS, which is the most common genetic type of ALS which is caused by a mutation in the C9orf72 gene. The mutation occurs when six letters of DNA that make up part of the gene’s genetic code – GGGGCC – are repeated hundreds of extra times. It is as if a single word is repeated hundreds of times in the same sentence. © 2010–2020, The Conversation US, Inc.

Related chapters from BN: Chapter 11: Motor Control and Plasticity; Chapter 13: Homeostasis: Active Regulation of the Internal Environment
Related chapters from MM:Chapter 5: The Sensorimotor System; Chapter 9: Homeostasis: Active Regulation of the Internal Environment
Link ID: 27379 - Posted: 07.21.2020

For every cell in the body there comes a time when it must decide what it wants to do for the rest of its life. In an article published in the journal PNAS, National Institutes of Health researchers report for the first time that ancient viral genes that were once considered “junk DNA” may play a role in this process. The article describes a series of preclinical experiments that showed how some human endogenous retrovirus (HERV-K) genes inscribed into chromosomes 12 and 19 may help control the differentiation, or maturation, of human stem cells into the trillions of neurons that are wired into our nervous systems. The experiments were performed by researchers in a lab led by Avindra Nath, M.D., clinical director, at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Over the course of evolution, the human genome has absorbed thousands of human endogenous retrovirus genes. As a result, nearly eight percent of the DNA that lines our chromosomes includes remnants of these genes. Although once thought to be inactive, or “junk”, recent studies have shown that these genes may be involved in human embryonic development, the growth of some tumors, and nerve damage during multiple sclerosis. Previously, researchers in Dr. Nath’s lab showed that amyotrophic lateral sclerosis (ALS) may be linked to activation of the HERV-K gene. In this study, led by Tongguang (David) Wang, M.D., Ph.D., staff scientist at NINDS, the team showed that deactivation of the gene may free stem cells to become neurons. The researchers performed most of their experiments on blood cells, drawn from healthy volunteers at the NIH’s Clinical Center, that they genetically transformed into induced pluripotent stem cells, which can then turn into any cell type in the body. Surprisingly, they found that the surfaces of the stem cells were lined with high levels of HERV-K, subtype HML-2, an envelope protein, that viruses often use to latch onto and infect cells. These proteins progressively disappeared as the cells were served two rounds of “cocktails.” One round nudged the cells into an intermediate, neural stem cell state followed by a second round that pushed the cells into finally becoming neurons.

Related chapters from BN: 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 4: Development of the Brain
Link ID: 27359 - Posted: 07.14.2020

Jon Hamilton The same process that causes dew drops to form on a blade of grass appears to play an important role in Alzheimer's disease and other brain diseases. The process, known as phase transition, is what allows water vapor to condense into liquid water, or even freeze into solid ice. That same sort of process allows brain cells to constantly reorganize their inner machinery. But in degenerative diseases that include amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's, the phase transitions inside neurons seem to go awry, says Dr. J. Paul Taylor, a neurogeneticist at St. Jude Children's Research Hospital in Memphis, and an investigator with the Howard Hughes Medical Institute. This malfunctioning prompts the interior of the cell to become too viscous, Taylor says. "It's as if you took a jar of honey [and] left it in the refrigerator overnight." In this sticky environment, structures that previously could nimbly disassemble and move around become "irreversibly glommed together," says Clifford Brangwynne, a professor of chemical and biological engineering at Princeton University and an investigator with the Howard Hughes Medical Institute. "And when they're irreversibly stuck like that, they can no longer leave to perform functions elsewhere in the cell." That glitch seems to allow toxins to begin to build up in and around these dysfunctional cells, Taylor says — including the toxins associated with Alzheimer's and other neurodegenerative diseases. The science behind this view of brain diseases has emerged only in the past decade. In 2009, Brangwynne was part of a team that published a study showing that phase transitions are important inside cells — or at least inside the reproductive cells of worms. © 2020 npr

Related chapters from BN: Chapter 7: Life-Span Development of the Brain and Behavior; Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 4: Development of the Brain; Chapter 5: The Sensorimotor System
Link ID: 27351 - Posted: 07.08.2020

Abby Olena Base editors, which convert one nucleotide to another without a double-strand DNA break, have the potential to treat diseases caused by mutant genes. One drawback, though, is that the DNA that encodes CRISPR base editors is long—too long to fit in the adeno-associated viruses (AAVs) most commonly used for gene therapy. In a study published in Molecular Therapy on January 13, researchers split the DNA encoding a base editor into two AAV vectors and injected them into a mouse model of inherited amyotrophic lateral sclerosis (ALS). The strategy disabled the disease-causing gene, improving the animals’ symptoms and prolonging their lives. “We’d like to be able to make gene editing tools that can fit inside an AAV vector. Unfortunately, some of the tools are so big that they can’t fit inside, so in this study, they were able to come up with a solution to that by using a split protein,” says David Segal, a biochemist at the University of California, Davis, who was not involved in the work. “It’s not the first time that that system has been used, but it’s the first time it’s been applied to this kind of base editor.” Pablo Perez-Pinera, a bioengineer at University of Illinois at Urbana-Champaign, and colleagues developed a strategy to split the base editor into two chunks. In a study published in 2019, they generated two different AAV vectors, each containing a portion of coding DNA for an adenine-to-thymine base editor. They also included sequences encoding so-called inteins—short peptides that when they are expressed within proteins stick together and cleave themselves out, a bit like introns in RNA. The researchers built the inteins into the vectors such that when the inteins produced by the two vectors dimerized, bringing the two base editor parts together, and then excised themselves, they left behind a full-length, functional base editor. © 1986–2020 The Scientist

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 27194 - Posted: 04.15.2020

Scientists say they have discovered a possible underlying cause of the neurological disorder, motor neurone disease (MND). The University of Exeter team says it has found evidence that MND is linked to an imbalance of cholesterol and other fats in cells. It says the research could lead to more accurate diagnosis and new treatments. MND affects around 5,000 people in the UK and causes more than 2,000 deaths a year. What is MND? Motor neurone disease is a group of diseases that affect the nerve cells in the brain and spinal cord that tell your muscles what to do. Also known as ALS, it causes muscle weakness and stiffness. Eventually people with the disease are unable to move, talk, swallow and finally, breathe. There is no cure and the exact causes are unclear - it's been variously linked to genes, exposure to heavy metals and agricultural pollution. What did the researchers find? Scientists at the University of Exeter say they had a "eureka moment" when they realised that 13 genes - which, if altered, can cause the condition - were directly involved in processing cholesterol. They say their theory could help predict the course and severity of the disease in patients and monitor the effect of potential new drugs. The theory is outlined in a paper, published in Brain: A Journal of Neurology. Lead author Prof Andrew Crosby said: "For years, we have known that a large number of genes are involved in motor neurone disease, but so far it hasn't been clear if there's a common underlying pathway that connects them." The finding particularly relates to what is known as the "spastic paraplegias", where the malfunction is in the upper part of the spinal cord. Dr Emma Baple, also from the University of Exeter Medical School, said: "Currently, there are no treatments available that can reverse or prevent progression of this group of disorders. Patients who are at high risk of motor neurone disease really want to know how their disease may progress and the age at which symptoms may develop, but that's very difficult to predict." © 2019 BBC

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 26902 - Posted: 12.18.2019

By Jonah Engel Bromwich Pete Frates, a former college baseball player whose participation in the social media phenomenon known as the Ice Bucket Challenge helped raise more than $100 million toward fighting amyotrophic lateral sclerosis, commonly known as A.L.S. or Lou Gehrig’s disease, died on Monday at his home in Beverly, Mass. He was 34. His death was announced in a statement by Boston College, his alma mater. Quoting his family, it said he died “after a heroic battle with A.L.S.” Mr. Frates learned he had the disease in 2012. A.L.S. attacks the body’s nerve cells and leads to full paralysis. Patients are typically expected to live for two to five years from the time of diagnosis. Mr. Frates did not create the Ice Bucket Challenge, in which participants dumped buckets of ice water over their heads while pledging to donate money to fight A.L.S. But a Facebook video in July 2014 showing him doing his version of the challenge — in which he bobbed his head to Vanilla Ice’s song “Ice Ice Baby” — prompted a surge in participation that summer, to where it became a viral sensation. LeBron James, Bill Gates, Oprah Winfrey and other celebrities stepped forward to be drenched, and millions of others followed suit. Mr. Frates became one of the most visible supporters of the effort, and in August 2014 he completed the challenge again (this time with ice water) at Fenway Park, along with members of the Boston Red Sox organization. The videos were inescapable for anyone on Facebook, and the A.L.S. Association, a Washington-based nonprofit that works to fight the disease, received more than $115 million. In 2015 the organization released an infographic showing how those funds were being spent. About $77 million, or 67 percent, of the money was used for research that ultimately identified the NEK1 gene, which contributes to the disease. The finding gave scientists guidance in developing treatment drugs. © 2019 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 26885 - Posted: 12.10.2019

By Tina Hesman Saey A newly discovered type of mitochondrial self-destruction may make some brain cells vulnerable to ALS, also known as Lou Gehrig’s disease. In mice genetically engineered to develop some forms of a degenerative nerve disease similar to amyotrophic lateral sclerosis, energy-generating organelles called mitochondria appear to dismantle themselves without help from usual cell demolition crews. This type of power plant self-destruction was spotted in upper motor neurons, brain nerve cells that help initiate and control movements, but not in neighboring cells, researchers report November 7 in Frontiers in Cellular Neuroscience. Death of those upper motor neurons is a hallmark of ALS, and the self-destructing mitochondria may be an early step that sets those cells up to die later. Pembe Hande Özdinler, a cellular neuroscientist at Northwestern University Feinberg School of Medicine in Chicago, and her colleagues have dubbed the mitochondrial dissolution “mitoautophagy.” It is a distinct process from mitophagy, the usual way that cellular structures called autophagosomes and lysosomes remove damaged mitochondria from the cell, Özdinler says. Usually, clearing out old or damaged mitochondria is important for cells to stay healthy. When mitochondria sustain too much damage, they may trigger the programmed death of the entire cell, known as apoptosis (SN: 8/9/18). Özdinler’s team spotted what she describes as “awkward” mitochondria in electron microscope images of upper motor neurons from 15-day-old mice. These unweaned mice are equivalent to human teenagers, Özdinler says. ALS typically doesn’t strike until people are 40 to 70 years old. But by the time symptoms appear, motor neurons are already damaged, so Özdinler’s group looked at the young mice to capture the earliest signs of the disease. © Society for Science & the Public 2000–2019

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 26804 - Posted: 11.08.2019

By Maya Vijayaraghavan On Jan. 1, my husband asked me whether he would die that year. I said no. It happened to be my birthday, and I wanted to feel jubilant despite the tragic turn of events in our life. I thought Rahul might have another year, that he might beat the odds of dying this year. In other words, his hazard ratio was favorable compared with someone else in his situation. He liked talking about something related, hazard scores — a composite score of one’s genetic risk for a particular outcome such as diagnosis of a disease. It was his thing as a neuroscientist-physician. He developed one for Alzheimer’s disease, and was on his way to developing one for amyotrophic lateral sclerosis (ALS), the disease he had been studying even before he got sick with it. In reality, he had declined significantly since his diagnosis of ALS two years prior. First, he lost his speech, then his mobility, and very quickly breathing became a struggle. But any talk of decline came with an acceptance that his life was imminently finite, and neither of us were willing to accept that outcome. But Rahul did die, six months after that conversation. I remember some of our last conversations, when things were very difficult. His forewarning that this existence with him teetering at the brink of life and death was much easier than the life I would lead as a widow, raising two young children. I think neither of us really understood that the emptiness I’d feel would be soul-crushing. That I would cry all the time. That I would miss him so much. That I would become a ghost of my former self. That this thing they call complicated grief, in which healing doesn’t occur as it’s supposed to, and which supposedly happens only after a year, is something that I feel now. That I would think constantly about the time when my husband was first diagnosed and he got into a fight with our then-3-year-old (now 5) about how he could not carry him because he did not have the strength to and not because he did not want to.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 26761 - Posted: 10.28.2019