Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget's disease, or a combination of these. The disease mechanism is unknown. We developed a Drosophila model of VCP mutation-dependent degeneration. The phenotype is reminiscent of PINK1 and parkin mutants, including a pronounced mitochondrial defect. Indeed, VCP interacts genetically with the PINK1/parkin pathway in vivo. Paradoxically, VCP complements PINK1 deficiency but not parkin deficiency. The basis of this paradox is resolved by mechanistic studies in vitro showing that VCP recruitment to damaged mitochondria requires Parkin-mediated ubiquitination of mitochondrial targets. VCP recruitment coincides temporally with mitochondrial fission, and VCP is required for proteasome-dependent degradation of Mitofusins in vitro and in vivo. Further, VCP and its adaptor Npl4/Ufd1 are required for clearance of damaged mitochondria via the PINK1/Parkin pathway, and this is impaired by pathogenic mutations in VCP.
Pubmed ID: 23498974 RIS Download
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The FlyTrap database presents the current results of large scale protein trapping screens that provide both information on which cells express each tagged gene, and subcellular localization of GFP-tagged proteins. Expression is under the control of endogenous promoter and enhancer elements, allowing for visualization of normal expression patterns. Drosophila proteins tagged with Green Fluorescent Protein (GFP) were created by insertion into genes of an artificial exon encoding GFP flanked by splice acceptor (SA) and splice donor (SD) sequences so that expression of GFP relies on splicing into mature mRNAs and in-frame fusion.
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