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Press release
Tuesday, February 16, 2021
An NIH-led study locates five genes that may play a critical role in Lewy body dementia.
In a study conducted by researchers at the National Institutes of Health, scientists found that five genes could play a critical role in determining whether a person would have Lewy body dementia, a devastating disorder that riddled the brain with clumps of deposits. of abnormal proteins called Lewy bodies. Lewy bodies are also a hallmark of Parkinson’s disease. The findings, published in Nature Genetics, not only confirmed the disease’s links to Parkinson’s disease, but also suggested that people with Lewy body dementia may share similar genetic profiles to those with Lewy body dementia. Alzheimer’s.
“Lewy body dementia is a devastating brain disorder for which we have no effective treatment. Patients often seem to suffer from the worst Alzheimer’s and Parkinson’s diseases. Our results support the idea that this may be due to the fact that Lewy body dementia is caused by a range of problems that can be seen in both disorders, ”said Sonja Scholz, MD, Ph.D., researcher at the NIH and Stroke National Institute of Neurological Disorders (NINDS) and the lead author of the study. “We hope that these results will serve as a model for understanding the disease and developing new treatments.”
The study was led by the team of Dr. Scholz and researchers in the lab of Bryan J. Traynor, MD, Ph.D., a senior investigator at the National Institute on Aging (NIA) at NIH.
Lewy body dementia usually affects people over the age of 65. The first signs of the disease include hallucinations, mood swings, and problems with thinking, moving, and sleeping. Patients who initially have cognitive and behavioral problems are usually diagnosed with Lewy body dementia, but are sometimes misdiagnosed with Alzheimer’s disease. Also, many patients who are initially diagnosed with Parkinson’s disease may eventually have thinking and mood difficulties caused by Lewy body dementia. In either case, as the disease worsens, patients become severely disabled and may die within eight years of diagnosis.
A growing body of evidence suggests that genetics may play a role in the disorder and that some cases can be inherited. Scientists have found that some of these rare cases can be caused by mutations in the alpha-synuclein (SNCA) gene, the main protein found in Lewy bodies. Other studies have shown that variants of the apolipoprotein E (APOE) gene, which is known to play a role in Alzheimer’s disease, may also play a role in Lewy body dementia.
“Compared to other neurodegenerative disorders, very little is known about the genetic forces behind Lewy body dementia,” said Dr. Traynor. “To better understand, we wanted to study the genetic architecture of Lewy body dementia.”
To do this, they compared the chromosomal DNA sequences of 2,981 patients with Lewy body dementia with those of 4,931 healthy control participants of the same age. Samples were collected from participants of European descent at 44 sites: 17 in Europe and 27 in North America. DNA sequencing was led by Clifton Dalgard, Ph.D., and researchers at the American Genome Center, a series of state-of-the-art laboratories at the Uniformed Services University of the Health Sciences and supported by the Henry M. Jackson Foundation for the Advancement of Military Medicine.
Initially, they found that the sequences of five genes in patients with Lewy body dementia were often different from those in controls, suggesting that these genes may be important. It was the first time that two of the genes, called BIN1 and TMEM175, had been involved in the disease. These genes may also have links with Alzheimer’s and Parkinson’s diseases. The other three genes, SNCA, APOE and GBA, had been implicated in previous studies and thus reinforced the importance of genes in Lewy body dementia.
The researchers also found differences in the same five genes when they compared the DNA sequences of 970 other Lewy body dementia patients with a new set of 8,928 control subjects, confirming their first results.
Further analysis has suggested that changes in the activity of these genes can lead to dementia and that the GBA gene can have a particularly strong influence on the disease. The gene encodes instructions for beta-glucosylceramidase, a protein that helps a cell’s recycling system break down sugary fats. Researchers have found that common and rare variants of the GBA gene are linked to Lewy body dementia.
“These results provide a list of five genes that we strongly suspect to play a role in Lewy body dementia,” said Dr. Traynor.
Finally, to examine the apparent links between Lewy body dementia and other neurodegenerative diseases, the researchers analyzed data in more detail from previous studies on Alzheimer’s disease and Parkinson’s disease. They found that the genetic profiles of the patients in this study were more likely to suffer from Alzheimer’s disease or Parkinson’s disease than control subjects of the same age. These predictions have held up even after reducing the potential impact of genes known to cause Alzheimer’s and Parkinson’s disease, like APOE and SNCA. Interestingly, the patient’s genetic risk profiles for Alzheimer’s disease, on the one hand, or Parkinson’s disease, on the other hand, did not overlap.
“Although Alzheimer’s disease and Parkinson’s disease are very different molecular and clinical disorders, our results support the idea that the problems causing these diseases can also occur in Lewy body dementia,” Dr Scholz said. “The challenge we face in treating these patients is to determine the specific issues that cause dementia. We hope studies like this will help doctors find specific treatments for each patient’s condition.
To help with this effort, the team published the study’s genome sequence data on the Genotypes and Phenotypes Database (dbGaP), a National Library of Medicine website that researchers can freely search for. new information on the causes of Lewy body dementia and other disorders.
Item:
Chia, R. et al. Genome sequencing analysis identifies novel loci associated with Lewy body dementia and provides information on the complex genetic architecture. Nature Genetics, February 15, 2021 DOI: 10.1038 / s41588-021-00785-3
This study was supported in part by the NIH intramural research programs at the National Institute of Neurological Disorders and Stroke (NS003154) and the National Institute on Aging (AG000935).
NINDS (https://www.ninds.nih.gov) is the largest funder of brain and nervous system research in the country. The mission of NINDS is to research fundamental knowledge about the brain and nervous system and to use this knowledge to reduce the burden of neurological disease.
About the National Institute on Aging (NIA): The NIA leads the efforts of the US federal government to conduct and support research on aging and the health and well-being of older adults. Visit the NIA website for information on a range of aging topics in English and Spanish. Learn more about age-related cognitive changes and neurodegenerative diseases through its Alzheimer’s Disease and Dementia Education and Reference Center (ADEAR) website. Stay connected with NIA!
About the National Institutes of Health (NIH):NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the premier federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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