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The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability
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 USP24 (ubiquitin specific peptidase 24), a gene located...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Taylor & Francis
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984603/ https://www.ncbi.nlm.nih.gov/pubmed/30957634 http://dx.doi.org/10.1080/15548627.2019.1598754 |
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author | Thayer, Julia A. Awad, Ola Hegdekar, Nivedita Sarkar, Chinmoy Tesfay, Henok Burt, Cameran Zeng, Xianmin Feldman, Ricardo A. Lipinski, Marta M. |
author_facet | Thayer, Julia A. Awad, Ola Hegdekar, Nivedita Sarkar, Chinmoy Tesfay, Henok Burt, Cameran Zeng, Xianmin Feldman, Ricardo A. Lipinski, Marta M. |
author_sort | Thayer, Julia A. |
collection | PubMed |
description | 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 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 |
format | Online Article Text |
id | pubmed-6984603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-69846032020-02-10 The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability Thayer, Julia A. Awad, Ola Hegdekar, Nivedita Sarkar, Chinmoy Tesfay, Henok Burt, Cameran Zeng, Xianmin Feldman, Ricardo A. Lipinski, Marta M. Autophagy Research Paper 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 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 Taylor & Francis 2019-04-07 /pmc/articles/PMC6984603/ /pubmed/30957634 http://dx.doi.org/10.1080/15548627.2019.1598754 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Research Paper Thayer, Julia A. Awad, Ola Hegdekar, Nivedita Sarkar, Chinmoy Tesfay, Henok Burt, Cameran Zeng, Xianmin Feldman, Ricardo A. Lipinski, Marta M. The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability |
title | The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability |
title_full | The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability |
title_fullStr | The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability |
title_full_unstemmed | The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability |
title_short | The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability |
title_sort | park10 gene usp24 is a negative regulator of autophagy and ulk1 protein stability |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984603/ https://www.ncbi.nlm.nih.gov/pubmed/30957634 http://dx.doi.org/10.1080/15548627.2019.1598754 |
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