Osellame, LD, Rahim, AA, Hargreaves, IP, Gegg, ME, Richard-Londt, A, Brandner, S, Waddington, SN, Schapira, AHV and Duchen, MR (2013) Mitochondria and Quality Control Defects in a Mouse Model of Gaucher Disease-Links to Parkinson's Disease. Cell Metabolism, 17 (6). pp. 941-953. ISSN 1550-4131

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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.

Item Type:	Article
Uncontrolled Keywords:	0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	Elsevier
Related URLs:	Author
Date Deposited:	22 Sep 2020 10:48
Last Modified:	04 Sep 2021 06:39
DOI or ID number:	10.1016/j.cmet.2013.04.014
URI:	https://researchonline.ljmu.ac.uk/id/eprint/13687

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