title: Mitochondria and quality control defects in a mouse model of Gaucher disease--links to Parkinson's disease.
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.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK; UCL Consortium for Mitochondrial Research, University College London, London WC1E 6BT, UK.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Osellame
authors.affiliation: Gene Transfer Technology Group, Institute for Women's Health, University College London, London WC1E 6BT, UK.
authors.forename: Ahad A
authors.initials: AA
authors.lastname: Rahim
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.affiliation: UCL Consortium for Mitochondrial Research, University College London, London WC1E 6BT, UK; Department of Clinical Neurosciences, UCL Institute of Neurology, Royal Free Campus, London NW3 2PF, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Gegg
authors.affiliation: Division of Neuropathology and Department of Neurodegenerative Diseases, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Richard-Londt
authors.affiliation: Division of Neuropathology and Department of Neurodegenerative Diseases, Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: Gene Transfer Technology Group, Institute for Women's Health, University College London, London WC1E 6BT, UK; School of Pathology, University of the Witwatersrand, Johannesburg 2000, South Africa.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.affiliation: UCL Consortium for Mitochondrial Research, University College London, London WC1E 6BT, UK; Department of Clinical Neurosciences, UCL Institute of Neurology, Royal Free Campus, London NW3 2PF, UK.
authors.forename: Anthony H V
authors.initials: AHV
authors.lastname: Schapira
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK; UCL Consortium for Mitochondrial Research, University College London, London WC1E 6BT, UK. Electronic address: m.duchen@ucl.ac.uk.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001343:Autophagy / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004579:Electron Transport; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism*; D005962:Glucosylceramidase / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000235:genetics*; D009474:Neurons / Q000166:cytology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D051844:alpha-Synuclein; D005962:Glucosylceramidase