New research has found five genes linked to Lewy Body depression, which support the link between that condition and both Parkinson’s disease and Alzheimer’s disease.
The study, led by researchers from the U.S. National Institutes of Health, was published online Feb. 15 in The genetics of nature.
“Lewy body depression is a terrible brain disorder for which we do not have effective treatments. Patients often appear to suffer from the worst of Alzheimer’s and Parkinson’s diseases,” said lead author Sonja Scholz, MD, PhD.
“Our results support the notion that this may be due to Lewy’s body depression caused by a spectrum of problems seen in both disorders,” she said. hopefully these results will serve as a plan for understanding the disease and developing new treatments. “
For the study, the researchers compared the chromosomal DNA sequences of 2981 patients with Lewy body dementia with those of 4391 healthy control participants, by age. Samples were collected from European ancestry partners at 44 sites (17 in Europe and 27 across North America).
Sequences of five genes may help determine if a person suffers from Lewy body depression. Credit: Scholz lab, NIH / NINDS
“We found strong genetic evidence that there are changes in the genes GBA, BIN1, TMEM175, SNCA-AS1, and APOE affect the risk for developing Lewy body dementia, ”said Scholz, head of the neurodegenerative diseases study unit at the National Institute of Neurological Disorders and Stroke (NINDS). Medscape Medical News.
This was the first of two of the genes – BIN1 and TMEM175 – has been involved in the disease. The other three genes, SNCA, APOE, and GBA, have been linked in previous studies, and thus, strengthened the importance of genes in Lewy body depression, the researchers report.
They also confirmed their results in a second analysis in which they observed differences in the same five genes in a further 970 patients with Lewy body depression vs. a new set of 8928 control subjects.
Research is still ongoing into the exact roles of these common risk variables, Scholz said. “What we do know at the moment is that they are involved in basic cellular processes, such as protein metabolism, protein contamination, energy and lipid metabolism, and others,” she said. “The end result is a loss of neuroprotective activity and a gain of toxic activities that culminate in protein uptake, mitochondrial respiratory capacity failure, inflammation and neuronal toxicity.”
These latest genetic findings confirm a strong link between Lewy body depression, Parkinson’s disease, and Alzheimer’s disease.
“Interestingly, the five risk loci we found have been shown to be linked to Lewy body depression either playing a role in Alzheimer’s disease or Parkinson’s disease,” Scholz noted.
“What seems to indicate that the genetic architecture of Lewy body depression is very complex. Not that a patient has all the genetic traits of Alzheimer’s and all the genetic features of Parkinson’s Disease. Instead, they only seem to engage in certain ways, some Alzheimer ‘s loci here, some Parkinson’ s loci there. this disease, and our study represents the first step in resolving this nuance. “
Although Alzheimer’s disease and Parkinson’s disorder are clinically very different, she said, “our results support the notion that the complications caused by these diseases may also occur in depression. The challenge we face in treating these patients is to determine what specific problems are causing depression.We hope that studies like this one will help doctors to find accurate treatments to look for the condition of each patient. “
The researchers say they hope changes and shared nodes in common disease pathways could be targeted for the development of disease-modifying therapies. “Knowing the molecular relationships between degenerative diseases will inform clinical trial design and help in drug replacement for a broad spectrum of diseases,” Scholz suggested.
She concluded: “Our main message home from this study is that Lewy body depression is a complex and polygenic genetic disease that intersects with molecules with Alzheimer’s disease and Parkinson’s disease. We have the raw data publicly so that other researchers can access and analyze the data with their own theories in mind.We hope that this will accelerate the speed of discovery in this area which is not enough. “
Referring to Medscape Medical News, James Beck, PhD, chief scientific officer at the Parkinson’s Foundation, said this is one of the largest reports of Lewy body dementia genetics.
“This is a very interesting paper that has done a lot of work to compile all this genetic information from patients with Lewy body dementia,” said Beck, who was not involved in the research.
He pointed out that the observations that some of the genes are also linked to Alzheimer’s or Parkinson’s connections are linked to clinical symptoms seen in the different conditions.
“Lewy body depression is seen as a condition that responds somewhere in the network between Alzheimer’s and Parkinson’s. We now recognize that there will be more specific subtypes of neurodegenerative diseases and genetic traces such as those reported here to help us with this. “
He noted that one of the genes revealed in this report, SNCA, an antisense gene for alpha synuclein, the protein at the heart of Lewy body depression and Parkinson’s disease.
“This antisense gene appears to be a controlling factor for alpha synuclein production and this could be a target for drugs to reduce that process,” Beck suggested.
“While not a silver bullet, this research is part of the process of developing an information resource that will provide in-depth treatment of neurodegenerative diseases,” Beck said. “It will guide us in identifying specific genetic targets. We need to think about the potential of different genes and mutations – what do they do and can they be changed? “
He said: “The great hope for the future is that we may be able to use genetic information in middle age to assess an individual’s risk of developing various neurodegenerative conditions, and also to develop specific therapies that can slow this process down. We are just at the beginning of that journey now that we are beginning to understand how genetics affects neurodegenerative diseases. ”
This research was supported in part by the National Institutes of Health Intramural Research Program, the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.
The genetics of nature. Published online February 15, 2021. Summary
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