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Cell Metab. 2013 Jun 4;17(6):941-53. doi: 10.1016/j.cmet.2013.04.014. Epub 2013 May 23.

Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson's disease.

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  • 1Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.

Abstract

Mutations in the glucocerebrosidase (gba) gene cause Gaucher disease (GD), the most common lysosomal storage disorder, and increase susceptibility to Parkinson's disease (PD). While the clinical and pathological features of idiopathic PD and PD related to gba (PD-GBA) mutations are very similar, cellular mechanisms underlying neurodegeneration in each are unclear. Using a mouse model of neuronopathic GD, we show that autophagic machinery and proteasomal machinery are defective in neurons and astrocytes lacking gba. Markers of neurodegeneration--p62/SQSTM1, ubiquitinated proteins, and insoluble α-synuclein--accumulate. Mitochondria were dysfunctional and fragmented, with impaired respiration, reduced respiratory chain complex activities, and a decreased potential maintained by reversal of the ATP synthase. Thus a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways. These data provide conclusive evidence for mitochondrial dysfunction in GD and provide insight into the pathogenesis of PD and PD-GBA.

PMID:
23707074
PMCID:
PMC3678026
DOI:
10.1016/j.cmet.2013.04.014
[PubMed - indexed for MEDLINE]
Free PMC Article
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