NIA researchers discovered that individuals with a DNA variant that has an effect only in an immune cell present in the brain, called microglia, have an increased risk of developing Parkinson’s disease. Their study results, published July 27 in Science Translational Medicine, suggest scientists should consider cell type when examining possible causes of Parkinson’s and other neurodegenerative disorders.
Microglia are special cells of the immune system that help protect the brain and nervous system by eating damaged cells or pathogens. The variant the researchers found originates in a region of DNA near the leucine-rich repeat kinase 2 (LRRK2) gene, but not inside of the gene. The researchers knew that mutations in the LRRK2 gene and in DNA regions close by LRRK2 contributed to Parkinson’s, but the mechanism for how these variants led to the development of the disease, as well as which cell types were involved, remained unknown.
To address the question, the researchers used brain samples that had previously been sequenced by the North American Brain Expression Consortium. The researchers performed single nuclei RNA sequencing to identify which types of cells in the brain had instructions for making the LRRK2 protein. Once they determined that multiple types of brain cells — including oligodendrocyte precursor cells, excitatory neurons, and microglia — could make lots of LRKK2 protein, they needed to verify which group of cells worked to increase the risk of Parkinson’s. The researchers established that one particular variant increased Parkinson’s risk through microglia, despite being present in many other cell types. The discovery advances the science a step closer to understanding the involvement of gene variants in disease progression.
Scientists have found that people who are members of families that develop late-stage Parkinson’s have mutations in the LRKK2 gene. The current results suggest that people who do not have a family history of the disease may benefit from therapies that inhibit LRKK2, currently in clinical trials. Additionally, the new findings imply microglia with dysfunctional LRKK2 protein may contribute to the inflammation and neuronal death seen in Parkinson’s.
This research was conducted by NIA Intramural Research Program scientists, projects ZIAAG000947 and Z01AG000949.