Researchers have discovered a new subtype of multiple sclerosis (MS), providing a better understanding of the disease and potentially opening the door to more personalized diagnosis and treatments.
Traditionally, demyelination of cerebral white matter is thought to stimulate neuronal degeneration and permanent neurological disability in patients with MS. However, brain magnetic resonance imaging (MRI) studies have indicated a possibility of demyelination and neuronal degeneration occurring independently. Now, new study findings have identified a subtype of MS—myelocortical MS (MCMS)—that has neuronal loss but no demyelination of the brain’s white matter.
“This study opens up a new arena in MS research,” said Bruce Trapp, PhD, chair, Cleveland Clinic’s Lerner Research Institute, and lead researcher of the study, in a statement. “It is the first to provide pathological evidence that neuronal degeneration can occur without white matter myelin loss in the brains of patients with the disease.”
Working with lab mice models of multiple sclerosis (MS), UC Davis scientists have detected a novel molecular target for the design of drugs that could be safer and more effective than current FDA-approved medications against MS.
The findings of the research study, published online today in the journal EMBO Molecular Medicine could have therapeutic applications for MS as well as cerebral palsy and leukodystrophies, all disorders associated with loss of white matter, which is the brain tissue that carries information between nerve cells in the brain and the spinal cord.
The target, a protein referred to as mitochondrial translocator protein (TSPO), had been previously identified but not linked to MS, an autoimmune disease that strips the protective fatty coating off nerve fibers of the brain and spinal cord. The mitrochronical TSPO is located on the outer surface of mitochondria, cellular structures that supply energy to the cells. Damage to the fatty coating, or myelin, slows the transmission of the nerve signals that enable body movement as well as sensory and cognitive functioning.
The scientists identified mitochondrial TSPO as a potential therapeutic target when mice that had symptoms of MS improved after being treated with the anti-anxiety drug etifoxine, which interacts with mitochondrial TSPO. When etifoxine, a drug clinically available in Europe, was administered to the MS mice before they had clinical signs of disease, the severity of the disease was reduced when compared to the untreated lab animals. When treated at the peak of disease severity, the animals' MS symptoms improved.
"Etifoxine has a novel protective effect against the loss of the sheath that insulates the nerve fibers that transmit the signals from brain cells," said Wenbin Deng, principal investigator of the study and associate professor of biochemistry and molecular medicine at UC Davis.
About 50 percent of people who reach the age of 85 will develop Alzheimer’s disease. Most will die within about five years of exhibiting the hallmark symptoms of the disease – severe memory loss and a precipitous decline in cognitive function.
But the molecular processes that lead to the disease will have begun years earlier.
Currently, there are no known ways to prevent the disease or to stop its progression once it has begun. But research at the University of Virginia offers new understanding of how the disease develops at the molecular level, long before extensive neuronal damage occurs and symptoms show up.
Additionally, the researchers have found that an FDA-approved drug, memantine, currently used only for alleviating the symptoms of moderate-to-severe Alzheimer’s disease, might be used to prevent or slow the progression of the disease if used before symptoms appear. The research also offers, based on extensive experimentation, a hypothesis as to why this might work.
The findings are published currently online in the journal Alzheimer’s & Dementia.
“Based on what we’ve learned so far, it is my opinion that we will never be able to cure Alzheimer’s disease by treating patients once they become symptomatic,” said George Bloom, a UVA professor and chair of the Department of Biology, who oversaw the study in his lab. “The best hope for conquering this disease is to first recognize patients who are at risk, and begin treating them prophylactically with new drugs and perhaps lifestyle adjustments that would reduce the rate at which the silent phase of the disease progresses.
“Ideally, we would prevent it from starting in the first place.”
Two new studies published by investigators from Brigham and Women’s Hospital illustrate that not all forms of amyloid-beta (Aβ) protein – the protein thought to initiate Alzheimer’s disease – play an equally menacing role in the progress of the disease. Using a new way of preparing and extracting the protein as well as a new technique to search for promising drug candidates, researchers have highlighted the importance of testing and targeting different forms of Aβ. Their work may help advance the search for more precise and effective drugs to prevent or halt the progress of Alzheimer’s disease.
“Many different efforts are currently underway to find treatments for Alzheimer’s disease, and anti-Aβ antibodies are currently the furthest advanced. But the question remains: what are the most important forms of Aβ to target? Our study points to some interesting answers,” said Dominic Walsh, PhD, a principal investigator in the Ann Romney Center.
Aβ protein can take forms ranging from monomers – single molecules – to twisted tangles of plaques that can pollute the brain and are large enough that they can be seen with a traditional microscope. Walsh compares monomers to single Lego bricks, which can start sticking together to form complex structures of varying sizes. The two recently published studies investigate how to find new potential therapeutics that can target the structures most likely to cause harm.
Most Alzheimer’s disease studies use synthetic Aβ to approximate what conditions in the brain of an Alzheimer’s patient might be like. A small number of researchers have used Aβ extracted from human brain, but the extraction process is crude. In a study published in Acta Neuropathologica in April, Walsh and colleagues developed a much gentler extraction protocol to prepare samples from subjects with Alzheimer’s disease. The team found that Aβ was far more abundant in traditional crude extracts, but that the bulk of the extracted Aβ was innocuous. In contrast, much less Aβ was obtained with the gentler protocol, but in this case most of the Aβ was toxic.
Most Alzheimer’s disease studies use synthetic Aβ to approximate what conditions in the brain of an Alzheimer’s patient might be like. NeuroscienceNews.com image is in the public domain.
In a second study published in Nature Communications in July, Walsh and colleagues developed a screening test to try to find potential drugs to target the toxic forms of Aβ. The new technique uses extracts of brain samples from Alzheimer’s disease patients and live-cell imaging of stem-cell derived brain cells to find promising therapeutics. The team reports on 1C22, an Aβ antibody that they found could protect against toxic forms of amyloid-beta more effectively than the most clinically advanced Alzheimer’s disease therapeutics currently in clinical trials.