One of the great mysteries of neuroscience may finally have an answer: Scientists at the University of Virginia School of Medicine have identified a potential explanation for the mysterious death of specific brain cells seen in Alzheimer's, Parkinson's and other neurodegenerative diseases.
The new research suggests that the cells may die because of naturally occurring gene variation in brain cells that were, until recently, assumed to be genetically identical. This variation -- called "somatic mosaicism" -- could explain why neurons in the temporal lobe are the first to die in Alzheimer's, for example, and why dopaminergic neurons are the first to die in Parkinson's.
"This has been a big open question in neuroscience, particularly in various neurodegenerative diseases," said neuroscientist Michael McConnell, PhD, of UVA's Center for Brain Immunology and Glia (BIG). "What is this selective vulnerability? What underlies it? And so now, with our work, the hypotheses moving forward are that it could be that different regions of the brain actually have a different garden of these [variations] in young individuals and that sets up different regions for decline later in life."
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.”