Abstract
ObjectiveVariants 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.MethodsWe 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.ResultsIn 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).InterpretationOur 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.
Highlights
Lewy body disorders (LBD) which include Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal loss in the substantia nigra (SN) and the presence of neuronal cytoplasmic inclusions composed predominantly of α-synuclein termed Lewy Bodies (LBs)[1,2,3]. α-synuclein immunoreactivity, including Lewy Body (LB), have been described as features seen in the neuropathology of several lysosomal storage disorders including notably Gaucher disease (GD), and Sandhoff disease, Tay Sachs disease, and Sanfilippo syndrome [4,5,6,7,8]
Our study indicates that variants in GBA, SMPD1 and MCOLN1 are associated with LB pathology
In the current study we performed a genetic analysis of four lysosomal storage disorder genes including GBA, HEXA, SMPD1, MCOLN1 in 231 brain autopsies from the New York Brain Bank at Columbia University
Summary
Lewy body disorders (LBD) which include Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal loss in the substantia nigra (SN) and the presence of neuronal cytoplasmic inclusions composed predominantly of α-synuclein termed Lewy Bodies (LBs)[1,2,3]. α-synuclein immunoreactivity, including LB, have been described as features seen in the neuropathology of several lysosomal storage disorders including notably Gaucher disease (GD), and Sandhoff disease, Tay Sachs disease, and Sanfilippo syndrome [4,5,6,7,8]. Heterozygosity for mutations in the gene encoding glucocerebrosidase (GBA), which cause Gaucher disease (GD), has been identified as a risk factor for both PD and DLB. A recent study that assessed the association of specific founder mutations in each of the lysosomal storage disorder genes HEXA, SMPD1 and MCOLN1, in 938 Ashkenazi Jewish (AJ) PD patients and 282 matched AJ controls, reported SMPD1 L302P as a risk factor for PD in the AJ population[12]. To determine whether variants in other lysosomal storage disease genes, in the same pathway as GBA, are associated with LBs we conducted an independent genetic study of the lysosomal storage disorder genes GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies from the New York Brain Bank at Columbia University. The functional effect of GBA mutations was determined by performing a biochemical analysis of GBA in a subset of brains
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