한빛사논문
Abstract
Nam Chul Kim1, 5, Emilie Tresse1, 5, Regina-Maria Kolaitis1, Amandine Molliex1, Ruth E. Thomas4, Nael H. Alami1, Bo Wang2, Aashish Joshi2, Rebecca B. Smith1, Gillian P. Ritson1, Brett J. Winborn1, Jennifer Moore1, Joo-Yong Lee3, Tso-Pang Yao3, Leo Pallanck4, Mondira Kundu2, J. Paul Taylor1,*
1 Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38120, USA
2 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38120, USA
3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
4 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
*Corresponding author : J. Paul Taylor
5 These authors contributed equally to this work
Summary
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.
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