Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease.

Autor:	Clark LN; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America; Center for Human Genetics, Columbia University, New York, New York, United States of America., Chan R; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America., Cheng R; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America., Liu X; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America., Park N; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America., Parmalee N; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America., Kisselev S; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America., Cortes E; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America., Torres PA; Department of Neurology, New York University School of Medicine, New York, New York, United States of America; Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America., Pastores GM; Department of Neurology, New York University School of Medicine, New York, New York, United States of America; Department of Pediatrics, New York University School of Medicine, New York, New York, United States of America., Vonsattel JP; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America., Alcalay R; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America., Marder K; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America., Honig LL; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America., Fahn S; Department of Neurology, Columbia University, New York, New York, United States of America., Mayeux R; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America; Department of Neurology, New York University School of Medicine, New York, New York, United States of America; Department of Neurology, Columbia University, New York, New York, United States of America; Department of Psychiatry, and Department of Statistics, Columbia University, New York, New York, United States of America; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America; Center for Human Genetics, Columbia University, New York, New York, United States of America., Shelanski M; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America., Di Paolo G; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America., Lee JH; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America; Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America; Center for Human Genetics, Columbia University, New York, New York, United States of America.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2015 May 01; Vol. 10 (5), pp. e0125204. Date of Electronic Publication: 2015 May 01 (Print Publication: 2015).
DOI:	10.1371/journal.pone.0125204
Abstrakt:	Objective: Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis. Methods: We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by 'gene wise' genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers. Results: In a 'gene-wise' analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03-4.14 x10(-5)). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p<0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying GBA mutations compared to controls (p range: p<0.05-p<0.01). Interpretation: Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology. Biochemical data comparing GBA mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies.
Databáze:	MEDLINE
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