Parkinson’s Risk Mutations Found Least in Brain

Most scientists who study brain conditions such as Parkinson’s naturally focus on the brain, but new research from the Van Andel Research Institute in Michigan shows that the obvious starting point is not the only way to go.

In the study “Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson’s disease etiology,” published in the journal Scientific Reports, scientists now say that collections of small DNA mutations, linked to the risk of Parkinson’s, can be found in liver, fat, immune, and developmental cells.

Parkinson’s disease is typically not linked to genetics, only five to 10 percent of cases are inherited. But researchers do believe that the condition may stem from an intricate interaction between some genes and the environment – which is why scientists continue to seek answers from the genome (genetic material present in a cell or organism).

Single nucleotide polymorphisms (SNPs – pronounced snips) are point mutations in the DNA that are used in the study of genetic risk. While a single change in the DNA does not lead to Parkinson’s, a collection of them might change cell and bodily processes to the degree that an increased risk appears. Patterns of accumulation may point scientists toward processes that contribute to disease development — and if mutations linked to the condition are shown to impact immune genes, it is likely that immune processes are involved.

But the majority of the tiny DNA alterations often appear in regions that do not directly code for a protein. Instead, they work to control the activity of other genes.

Gerry Coetzee, PhD, a professor at Van Andel and senior author of the study, partnered with colleagues at Cedars-Sinai in Los Angeles to analyze SNPs previously identified in large genome-wide association studies (GWAS). Other scientists already showed that SNPs were linked to Parkinson’s, but to get a hint of disease processes the Van Andel team sought to learn how they affected the function of various cells.

Though previously done for different diseases, it was only possible to assess for one cell type at a time. With the help of the Roadmap Epigenomics Mapping Consortium, which makes genetic material accessible to scientists, it is now possible to study the effects of risk mutations in many cell types.

Analyzing 21 already identified risk areas, in DNA stretches where the mutations collect in 77 cell types, the team found 12 areas jammed with mutations. The finding is typically expected in Parkinson’s but only one of the areas was found located in the brain — the other 11 were spread across liver, fat, immune, and developmental cells.

“When we looked at the data, we were quite surprised to see the variation in tissue types,” said Coetzee, “Ultimately, if we can more precisely define risk factors for Parkinson’s, we can develop ways to mitigate them early on. We still have a long way to go but these findings are some of the first steps down that path.”

With three of the risk areas turning up in immune cells, the findings emphasize other recent research showing that inflammation might be involved in brain changes leading to disease.

“The emerging view is that Parkinson’s is more of a syndrome — a defined set of clinical symptoms and some shared features of brain pathology — with a diverse set of underlying causes,” said Dr. Patrik Brundin, PhD, director of the Van Andel Center for Neurodegenerative Science, and a study co-author.

As a syndrome, the disease could turn out to be a potluck of various bodily processes.

“This supports the emerging theory that Parkinson’s is a disorder that can be caused by disruptions in cellular processes in many locations, not just one, said Brundin. “Furthermore, for the disease to develop in one person there has to be an unfortunate combination of a genetic predisposition and, as yet undefined, environmental insults.”