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New Study Links Nerve Immune Cells With Parkinson's Disease Risk Mutation

A new study in this week's Science Translational Medicine sheds light on how the gene LRRK2, which has been closely linked with Parkinson's disease, affects disease progression. Genome-wide association studies have linked Parkinson's disease risk to coding mutations in LRRK2, as well as a common noncoding variation in the 5' region of the LRRK2 locus, yet the mechanisms underlying these associations are unclear. In the new study, a group of National Institutes of Health scientists used RNA sequencing to analyze donor brain samples and stem cell-derived brain cells, finding that the Parkinson's disease risk stemming from the LRRK2 noncoding mutation is specifically propagated through microglia and not by other cell types that express LRRK2 in the human brain. They also found that microglia harbor regulatory regions that influence the expression of LRRK2 in several brain regions. A CRISPR interference screen, meanwhile, revealed that a regulatory DNA element containing a single-nucleotide variant, dubbed, rs6581593 influences LRRK2 expression in microglia. "Our study demonstrates that cell type should be considered when evaluating the role of noncoding variation in disease pathogenesis," the authors write.