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Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage.

ABSTRACT: Mutations of the gene for glucocerebrosidase 1 (GBA) cause Gaucher disease (GD), an autosomal recessive lysosomal storage disorder. Individuals with homozygous or heterozygous (carrier) mutations of GBA have a significantly increased risk for the development of Parkinson's disease (PD), with clinical and pathological features that mirror the sporadic disease. The mechanisms whereby GBA mutations induce dopaminergic cell death and Lewy body formation are unknown. There is evidence of mitochondrial dysfunction and oxidative stress in PD and so we have investigated the impact of glucocerebrosidase (GCase) inhibition on these parameters to determine if there may be a relationship of GBA loss-of-function mutations to the known pathogenetic pathways in PD. We have used exposure to a specific inhibitor (conduritol-?-epoxide, C?E) of GCase activity in a human dopaminergic cell line to identify the biochemical abnormalities that follow GCase inhibition. We show that GCase inhibition leads to decreased ADP phosphorylation, reduced mitochondrial membrane potential and increased free radical formation and damage, together with accumulation of alpha-synuclein. Taken together, inhibition of GCase by C?E induces abnormalities in mitochondrial function and oxidative stress in our cell culture model. We suggest that GBA mutations and reduced GCase activity may increase the risk for PD by inducing these same abnormalities in PD brain.

SUBMITTER: Cleeter MW

PROVIDER: S-EPMC3550523 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage.

Cleeter Michael W J MW Chau Kai-Yin KY Gluck Caroline C Mehta Atul A Hughes Derralynn A DA Duchen Michael M Wood Nicholas William NW Hardy John J Mark Cooper J J Schapira Anthony Henry AH

Neurochemistry international 20121023 1

Mutations of the gene for glucocerebrosidase 1 (GBA) cause Gaucher disease (GD), an autosomal recessive lysosomal storage disorder. Individuals with homozygous or heterozygous (carrier) mutations of GBA have a significantly increased risk for the development of Parkinson's disease (PD), with clinical and pathological features that mirror the sporadic disease. The mechanisms whereby GBA mutations induce dopaminergic cell death and Lewy body formation are unknown. There is evidence of mitochondria ...[more]

PMID: 23099359

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Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage.

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Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage.

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