NIH-led study locates five genes that may play essential role in Lewy body dementia – sciencedaily

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In a study conducted by researchers at the National Institutes of Health (NIH), scientists found that five genes can play a critical role in determining whether a person will suffer from Lewy Body Dementia, a devastating disorder that plagues the brain of clumps of abnormal protein deposits called Lewy bodies. Lewy bodies are also a hallmark of Parkinson’s disease. The results, published in Genetics of nature, not only supported 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 Alzheimer’s disease.

“Lewy body dementia is a devastating brain disorder for which we have no effective treatment. Patients often seem to suffer from the worst of Alzheimer’s and Parkinson’s diseases. Our results support the idea that this may be because Lewy body dementia is caused by a spectrum of problems that can be seen in both disorders, ”said Sonja Scholz, MD, Ph.D., researcher at the NIH National Institute of Neurological Disorders and Stroke (NINDS) and 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 principal investigator at the NIH National Institute on Aging (NIA).

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, movement, and sleeping. Patients who initially have cognitive and behavioral problems are usually diagnosed as having Lewy body dementia, but are sometimes misdiagnosed with Alzheimer’s disease. Alternatively, many patients, who are initially diagnosed with Parkinson’s disease, may eventually have difficulty thinking and mood caused by Lewy body dementia. In either case, as the disease worsens, patients become severely disabled and may die within 8 years of diagnosis.

A growing body of evidence suggests that genetics may play a role in the disease 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 cutting-edge laboratories at the Uniformed Services University of the Health Sciences and supported by 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 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 further analyzed data from previous studies of Alzheimer’s disease and Parkinson’s disease. They found that the genetic profiles of the patients in this study were more likely to have Alzheimer’s disease or Parkinson’s disease than control subjects of the same age. These predictions held firm even after reducing the potential impact of genes known to cause Alzheimer’s and Parkinson’s disease, such as 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 that cause these diseases can also occur in Lewy body dementia,” said Dr. Scholz. “The challenge we face in treating these patients is to determine what specific problems are causing the dementia. We hope that studies like this will help doctors find specific treatments for the condition. each patient. “

To help with this effort, the team published the study’s genome sequence data on the Genotype and Phenotype Database (dbGaP), a National Library of Medicine website that researchers can search for. freely new information on the causes of Lewy body dementia and other disorders.

This study was funded in part by the NIH intramural research programs of the National Institute of Neurological Disorders and Stroke (NS003154) and the National Institute on Aging (AG000935).


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