The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity

Abstract

Dysfunctional mitochondria characterise Parkinson’s Disease (PD). Uncovering etiological molecules, which harm the homeostasis of mitochondria in response to pathological cues, is therefore pivotal to inform early diagnosis and therapy in the condition, especially in its idiopathic forms. This study proposes the 18 kDa Translocator Protein (TSPO) to be one of those. Both in vitro and in vivo data show that neurotoxins, which phenotypically mimic PD, increase TSPO to enhance cellular redox-stress, susceptibility to dopamine-induced cell death, and repression of ubiquitin-dependent mitophagy. TSPO amplifies the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signalling, forming positive feedback, which represses the transcription factor EB (TFEB) and the controlled production of lysosomes. Finally, genetic variances in the transcriptome confirm that TSPO is required to alter the autophagy–lysosomal pathway during neurotoxicity.

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Item Type:	Article
Authors/Creators:	Frison, M. Faccenda, D. Abeti, R. Rigon, M. Strobbe, D. England-Rendon, B.S. Cash, D. Barnes, K. Sadeghian, M. Sajic, M. Wells, L.A. Xia, D. Giunti, P. Smith, K. Mortiboys, H. https://orcid.org/0000-0001-6439-0579 Turkheimer, F.E. Campanella, M.
Copyright, Publisher and Additional Information:	© The Author(s), under exclusive licence to Springer Nature Limited 2021. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: July 2021 Published (online): 4 March 2021 Accepted: 5 February 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Funding Information:	Funder Grant number PARKINSONS UK F-1301
Depositing User:	Symplectic Sheffield
Date Deposited:	25 Mar 2021 11:54
Last Modified:	15 Feb 2022 11:40
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41380-021-01050-z
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:172445

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The translocator protein (TSPO) is prodromal to mitophagy loss in neurotoxicity

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