Abstract
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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Validation Study
MeSH terms
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Adaptor Proteins, Vesicular Transport
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / metabolism*
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Animals
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Animals, Genetically Modified
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Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cells, Cultured
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Drosophila
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Embryo, Mammalian
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Enzyme Inhibitors / pharmacology
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GTP Phosphohydrolases / metabolism
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Ganglia, Spinal / cytology
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Gene Expression Regulation / genetics
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HSP72 Heat-Shock Proteins / genetics
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Humans
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Immunoprecipitation
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins
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Leupeptins / pharmacology
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Microscopy, Electron, Transmission
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Mitochondria / drug effects
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Mitochondria / genetics*
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Mitochondria / metabolism
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Mitochondria / ultrastructure
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Mitochondrial Membrane Transport Proteins / metabolism
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Mutation / genetics
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Neuromuscular Junction / genetics
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Neuromuscular Junction / metabolism
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Neurons / metabolism*
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Neurons / ultrastructure
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Nuclear Proteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein Tyrosine Phosphatases / genetics
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Proteins / metabolism
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Proton Ionophores / pharmacology
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / pharmacology
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination / genetics
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Valosin Containing Protein
Substances
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Adaptor Proteins, Vesicular Transport
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Cell Cycle Proteins
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Drosophila Proteins
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Enzyme Inhibitors
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GAL4 protein, Drosophila
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HSP72 Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Leupeptins
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Luminescent Proteins
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Mitochondrial Membrane Transport Proteins
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NPLOC4 protein, human
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Nuclear Proteins
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Proteins
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Proton Ionophores
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RNA, Small Interfering
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Transcription Factors
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UFD1 protein, human
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Carbonyl Cyanide m-Chlorophenyl Hydrazone
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Ubiquitin-Protein Ligases
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PINK1 protein, Drosophila
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Protein Serine-Threonine Kinases
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EDTP protein, Drosophila
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Protein Tyrosine Phosphatases
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Adenosine Triphosphatases
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GTP Phosphohydrolases
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VCP protein, human
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Valosin Containing Protein
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Mfn1 protein, human
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park protein, Drosophila
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde