The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability
Identifieur interne : 000372 ( Main/Exploration ); précédent : 000371; suivant : 000373The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability
Auteurs : Julia A. Thayer [États-Unis] ; Ola Awad ; Nivedita Hegdekar [États-Unis] ; Chinmoy Sarkar [États-Unis] ; Henok Tesfay [États-Unis] ; Cameran Burt [États-Unis] ; Xianmin Zeng [États-Unis] ; Ricardo A. Feldman ; Marta M. Lipinski [États-Unis]Source :
- Autophagy [ 1554-8627 ] ; 2019.
Abstract
Recent 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
Url:
DOI: 10.1080/15548627.2019.1598754
PubMed: 30957634
PubMed Central: 6984603
Affiliations:
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Thayer</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Awad, Ola" sort="Awad, Ola" uniqKey="Awad O" first="Ola" last="Awad">Ola Awad</name><affiliation><nlm:aff id="AFF0002"><institution>Department of Microbiology and Immunology</institution></nlm:aff></affiliation></author><author><name sortKey="Hegdekar, Nivedita" sort="Hegdekar, Nivedita" uniqKey="Hegdekar N" first="Nivedita" last="Hegdekar">Nivedita Hegdekar</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sarkar, Chinmoy" sort="Sarkar, Chinmoy" uniqKey="Sarkar C" first="Chinmoy" last="Sarkar">Chinmoy Sarkar</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tesfay, Henok" sort="Tesfay, Henok" uniqKey="Tesfay H" first="Henok" last="Tesfay">Henok Tesfay</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Burt, Cameran" sort="Burt, Cameran" uniqKey="Burt C" first="Cameran" last="Burt">Cameran Burt</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zeng, Xianmin" sort="Zeng, Xianmin" uniqKey="Zeng X" first="Xianmin" last="Zeng">Xianmin Zeng</name><affiliation wicri:level="1"><nlm:aff id="AFF0003"><institution>XCell Science Inc</institution>, Novato, CA,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Feldman, Ricardo A" sort="Feldman, Ricardo A" uniqKey="Feldman R" first="Ricardo A." last="Feldman">Ricardo A. 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Lipinski</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AFF0004"><institution>Department of Anatomy and Neurobiology, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30957634</idno><idno type="pmc">6984603</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984603</idno><idno type="RBID">PMC:6984603</idno><idno type="doi">10.1080/15548627.2019.1598754</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000413</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000413</idno><idno type="wicri:Area/Pmc/Curation">000413</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000413</idno><idno type="wicri:Area/Pmc/Checkpoint">000335</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000335</idno><idno type="wicri:Area/Ncbi/Merge">000526</idno><idno type="wicri:Area/Ncbi/Curation">000526</idno><idno type="wicri:Area/Ncbi/Checkpoint">000526</idno><idno type="wicri:Area/Main/Merge">000372</idno><idno type="wicri:Area/Main/Curation">000372</idno><idno type="wicri:Area/Main/Exploration">000372</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The <italic>PARK10</italic> gene <italic>USP24</italic> is a negative regulator of autophagy and ULK1 protein stability</title><author><name sortKey="Thayer, Julia A" sort="Thayer, Julia A" uniqKey="Thayer J" first="Julia A." last="Thayer">Julia A. Thayer</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Awad, Ola" sort="Awad, Ola" uniqKey="Awad O" first="Ola" last="Awad">Ola Awad</name><affiliation><nlm:aff id="AFF0002"><institution>Department of Microbiology and Immunology</institution></nlm:aff></affiliation></author><author><name sortKey="Hegdekar, Nivedita" sort="Hegdekar, Nivedita" uniqKey="Hegdekar N" first="Nivedita" last="Hegdekar">Nivedita Hegdekar</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sarkar, Chinmoy" sort="Sarkar, Chinmoy" uniqKey="Sarkar C" first="Chinmoy" last="Sarkar">Chinmoy Sarkar</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tesfay, Henok" sort="Tesfay, Henok" uniqKey="Tesfay H" first="Henok" last="Tesfay">Henok Tesfay</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Burt, Cameran" sort="Burt, Cameran" uniqKey="Burt C" first="Cameran" last="Burt">Cameran Burt</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zeng, Xianmin" sort="Zeng, Xianmin" uniqKey="Zeng X" first="Xianmin" last="Zeng">Xianmin Zeng</name><affiliation wicri:level="1"><nlm:aff id="AFF0003"><institution>XCell Science Inc</institution>, Novato, CA,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Feldman, Ricardo A" sort="Feldman, Ricardo A" uniqKey="Feldman R" first="Ricardo A." last="Feldman">Ricardo A. Feldman</name><affiliation><nlm:aff id="AFF0002"><institution>Department of Microbiology and Immunology</institution></nlm:aff></affiliation></author><author><name sortKey="Lipinski, Marta M" sort="Lipinski, Marta M" uniqKey="Lipinski M" first="Marta M." last="Lipinski">Marta M. Lipinski</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Department of Anesthesiology & Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="AFF0004"><institution>Department of Anatomy and Neurobiology, University of Maryland School of Medicine</institution>, Baltimore, MD,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Autophagy</title><idno type="ISSN">1554-8627</idno><idno type="eISSN">1554-8635</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>Recent 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 <italic>USP24</italic> (ubiquitin specific peptidase 24), a gene located in the <italic>PARK10</italic> (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 <italic>USP24</italic> 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, <italic>USP24</italic> knockdown also improved neurite extension and/or maintenance in aged iPSC-derived dopaminergic neurons. Furthermore, we observed elevated levels of USP24 in the <italic>substantia nigra</italic> of a subpopulation of idiopathic PD patients, suggesting that USP24 may negatively regulate autophagy in PD.</p><p><bold>Abbreviations</bold>: Bafilomycin/BafA: bafilomycin A<sub>1</sub>; 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</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Levine, B" uniqKey="Levine B">B Levine</name></author><author><name sortKey="Klionsky, Dj" uniqKey="Klionsky D">DJ. 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first="Ola" last="Awad">Ola Awad</name><name sortKey="Feldman, Ricardo A" sort="Feldman, Ricardo A" uniqKey="Feldman R" first="Ricardo A." last="Feldman">Ricardo A. Feldman</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Thayer, Julia A" sort="Thayer, Julia A" uniqKey="Thayer J" first="Julia A." last="Thayer">Julia A. Thayer</name></noRegion><name sortKey="Burt, Cameran" sort="Burt, Cameran" uniqKey="Burt C" first="Cameran" last="Burt">Cameran Burt</name><name sortKey="Hegdekar, Nivedita" sort="Hegdekar, Nivedita" uniqKey="Hegdekar N" first="Nivedita" last="Hegdekar">Nivedita Hegdekar</name><name sortKey="Lipinski, Marta M" sort="Lipinski, Marta M" uniqKey="Lipinski M" first="Marta M." last="Lipinski">Marta M. Lipinski</name><name sortKey="Lipinski, Marta M" sort="Lipinski, Marta M" uniqKey="Lipinski M" first="Marta M." last="Lipinski">Marta M. Lipinski</name><name sortKey="Sarkar, Chinmoy" sort="Sarkar, Chinmoy" uniqKey="Sarkar C" first="Chinmoy" last="Sarkar">Chinmoy Sarkar</name><name sortKey="Tesfay, Henok" sort="Tesfay, Henok" uniqKey="Tesfay H" first="Henok" last="Tesfay">Henok Tesfay</name><name sortKey="Zeng, Xianmin" sort="Zeng, Xianmin" uniqKey="Zeng X" first="Xianmin" last="Zeng">Xianmin Zeng</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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