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dc.contributor.authorThayer, J.A.
dc.contributor.authorAwad, O.
dc.contributor.authorHegdekar, N.
dc.date.accessioned2019-09-13T17:02:31Z
dc.date.available2019-09-13T17:02:31Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85063972487&doi=10.1080%2f15548627.2019.1598754&partnerID=40&md5=136dcc8ba710f1763e83295e3cff9a55
dc.identifier.urihttp://hdl.handle.net/10713/10794
dc.description.abstractRecent studies indicate a causative relationship between defects in autophagy and dopaminergic neuron degeneration in Parkinson disease (PD). However, it is not fully understood how autophagy is regulated in the context of PD. Here we identify USP24 (ubiquitin specific peptidase 24), a gene located in the PARK10 (Parkinson disease 10 [susceptibility]) locus associated with late onset PD, as a novel negative regulator of autophagy. Our data indicate that USP24 regulates autophagy by affecting ubiquitination and stability of the ULK1 protein. Knockdown of USP24 in cell lines and in human induced-pluripotent stem cells (iPSC) differentiated into dopaminergic neurons resulted in elevated ULK1 protein levels and increased autophagy flux in a manner independent of MTORC1 but dependent on the class III phosphatidylinositol 3-kinase (PtdIns3K) activity. Surprisingly, USP24 knockdown also improved neurite extension and/or maintenance in aged iPSC-derived dopaminergic neurons. Furthermore, we observed elevated levels of USP24 in the substantia nigra of a subpopulation of idiopathic PD patients, suggesting that USP24 may negatively regulate autophagy in PD. Abbreviations: Bafilomycin/BafA: bafilomycin A 1 ; DUB: deubiquitinating enzyme; iPSC: induced pluripotent stem cells; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; nt: non-targeting; PD: Parkinson disease; p-ATG13: phospho-ATG13; PtdIns3P: phosphatidylinositol 3-phosphate; RPS6: ribosomal protein S6; SNPs: single nucleotide polymorphisms; TH: tyrosine hydroxylase; USP24: ubiquitin specific peptidase 24. Copyright 2019 The Author(s).en_US
dc.description.urihttps://doi.org/10.1080/15548627.2019.1598754en_US
dc.language.isoen-USen_US
dc.publisherTaylor and Francis Inc.en_US
dc.relation.ispartofAutophagy
dc.subjectAutophagyen_US
dc.subjectdopaminergic neuronsen_US
dc.subjectinduced-pluripotent stem cellsen_US
dc.subjectParkinson diseaseen_US
dc.subjectUSP24en_US
dc.titleThe PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stabilityen_US
dc.typeArticleen_US
dc.identifier.doi10.1080/15548627.2019.1598754


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