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Nat Med. 2016 Jan;22(1):54-63. doi: 10.1038/nm.3983. Epub 2015 Nov 30.

Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes.

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Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
Center for Mitochondrial Diseases, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Institute of Clinical Neurosciences, Southmead Hospital, University of Bristol, Bristol, UK.
Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland.
The Henry Wellcome Integrated Signaling Laboratories, School of Biochemistry, University of Bristol, Bristol, UK.
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Contributed equally


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.

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