title: Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes.
abstract: Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Wenzhang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.|Center for Mitochondrial Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Hoppel
authors.affiliation: Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Whone
authors.affiliation: Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Caldwell
authors.affiliation: The Henry Wellcome Integrated Signaling Laboratories, School of Biochemistry, University of Bristol, Bristol, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cullen
authors.affiliation: Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D034281:Dynamins / Q000378:metabolism; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D005455:Fluorescent Antibody Technique; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013378:Substantia Nigra / Q000166:cytology; D059008:Time-Lapse Imaging; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins