Association of a common genetic variant with Parkinson's disease is mediated by microglia.

Autor:	Langston RG; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.; University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA., Beilina A; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA., Reed X; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD 20892, USA., Kaganovich A; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA., Singleton AB; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD 20892, USA., Blauwendraat C; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.; Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD 20892, USA., Gibbs JR; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA., Cookson MR; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2022 Jul 27; Vol. 14 (655), pp. eabp8869. Date of Electronic Publication: 2022 Jul 27.
DOI:	10.1126/scitranslmed.abp8869
Abstrakt:	Studies of multiple neurodegenerative disorders have identified many genetic variants that are associated with risk of disease throughout a lifetime. For example, Parkinson's disease (PD) risk is attributed in part to both coding mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene and to a common noncoding variation in the 5' region of the LRRK2 locus, as identified by genome-wide association studies (GWAS). However, the mechanisms linking GWAS variants to pathogenicity are largely unknown. Here, we found that the influence of PD-associated noncoding variation on LRRK2 expression is specifically propagated through microglia and not by other cell types that express LRRK2 in the human brain. We find microglia-specific regulatory chromatin regions that modulate the LRRK2 expression in human frontal cortex and substantia nigra and confirm these results in a human-induced pluripotent stem cell-derived microglia model. We showed, using a large-scale clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen, that a regulatory DNA element containing the single-nucleotide variant rs6581593 influences the LRRK2 expression in microglia. Our study demonstrates that cell type should be considered when evaluating the role of noncoding variation in disease pathogenesis and sheds light on the mechanism underlying the association of the 5' region of LRRK2 with PD risk.
Databáze:	MEDLINE
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