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Citation
Kim, N.C., Tresse, E., Kolaitis, R.M., Molliex, A., Thomas, R.E., Alami, N.H., Wang, B., Joshi, A., Smith, R.B., Ritson, G.P., Winborn, B.J., Moore, J., Lee, J.Y., Yao, T.P., Pallanck, L., Kundu, M., Taylor, J.P. (2013). VCP Is Essential for Mitochondrial Quality Control by PINK1/Parkin and this Function Is Impaired by VCP Mutations.  Neuron 78(1): 65--80.
FlyBase ID
FBrf0221255
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC3683300 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Neuron
    Title
    Neuron
    Publication Year
    1988-
    ISBN/ISSN
    0896-6273
    Data From Reference
    Alleles (9)
    Genes (5)
    Human Disease Models (4)
    Physical Interactions (2)
    Natural transposons (1)
    Insertions (3)
    Experimental Tools (2)
    Transgenic Constructs (4)