Translocator protein (TSPO) ligands attenuate mitophagy deficits in the SH-SY5Y cellular model of Alzheimer's disease via the autophagy adaptor P62.

Fairley, LH; Grimm, A; Herff, SA; Eckert, A

Translocator protein (TSPO) ligands attenuate mitophagy deficits in the SH-SY5Y cellular model of Alzheimer's disease via the autophagy adaptor P62.

Fairley, LH Grimm, A Herff, SA Eckert, A

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Biochimie, 2024, 224, pp. 132-138
Issue Date:: 2024-09

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Field	Value	Language
dc.contributor.author	Fairley, LH
dc.contributor.author	Grimm, A
dc.contributor.author	Herff, SA
dc.contributor.author	Eckert, A
dc.date.accessioned	2025-01-21T04:02:49Z
dc.date.available	2024-01-18
dc.date.available	2025-01-21T04:02:49Z
dc.date.issued	2024-09
dc.identifier.citation	Biochimie, 2024, 224, pp. 132-138
dc.identifier.issn	0300-9084
dc.identifier.issn	1638-6183
dc.identifier.uri	http://hdl.handle.net/10453/183940
dc.description.abstract	Mitochondrial dysfunction has been widely implicated in the pathogenesis of Alzheimer's disease (AD), with accumulation of damaged and dysfunctional mitochondria occurring early in the disease. Mitophagy, which governs mitochondrial turnover and quality control, is impaired in the AD brain, and strategies aimed at enhancing mitophagy have been identified as promising therapeutic targets. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is upregulated in AD, and ligands targeting TSPO have been shown to exert neuroprotective effects in mouse models of AD. However, whether TSPO ligands modulate mitophagy in AD has not been explored. Here, we provide evidence that the TSPO-specific ligands Ro5-4864 and XBD173 attenuate mitophagy deficits and mitochondrial fragmentation in a cellular model of AD overexpressing the human amyloid precursor protein (APP). Ro5-4864 and XBD173 appear to enhance mitophagy via modulation of the autophagic cargo receptor P62/SQSTM1, in the absence of an effect on PARK2, PINK1, or LC3 level. Taken together, these findings indicate that TSPO ligands may be promising therapeutic agents for ameliorating mitophagy deficits in AD.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Biochimie
dc.relation.isbasedon	10.1016/j.biochi.2024.01.012
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.mesh	Humans
dc.subject.mesh	Mitophagy
dc.subject.mesh	Alzheimer Disease
dc.subject.mesh	Receptors, GABA
dc.subject.mesh	Sequestosome-1 Protein
dc.subject.mesh	Benzodiazepinones
dc.subject.mesh	Ligands
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Mitochondria
dc.subject.mesh	Autophagy
dc.subject.mesh	Amyloid beta-Protein Precursor
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Mitochondria
dc.subject.mesh	Humans
dc.subject.mesh	Alzheimer Disease
dc.subject.mesh	Benzodiazepinones
dc.subject.mesh	Amyloid beta-Protein Precursor
dc.subject.mesh	Receptors, GABA
dc.subject.mesh	Ligands
dc.subject.mesh	Autophagy
dc.subject.mesh	Sequestosome-1 Protein
dc.subject.mesh	Mitophagy
dc.subject.mesh	Humans
dc.subject.mesh	Mitophagy
dc.subject.mesh	Alzheimer Disease
dc.subject.mesh	Receptors, GABA
dc.subject.mesh	Sequestosome-1 Protein
dc.subject.mesh	Benzodiazepinones
dc.subject.mesh	Ligands
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Mitochondria
dc.subject.mesh	Autophagy
dc.subject.mesh	Amyloid beta-Protein Precursor
dc.title	Translocator protein (TSPO) ligands attenuate mitophagy deficits in the SH-SY5Y cellular model of Alzheimer's disease via the autophagy adaptor P62.
dc.type	Journal Article
utslib.citation.volume	224
utslib.location.activity	France
utslib.for	0601 Biochemistry and Cell Biology
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-01-21T04:02:48Z
pubs.publication-status	Published
pubs.volume	224

Abstract:

Mitochondrial dysfunction has been widely implicated in the pathogenesis of Alzheimer's disease (AD), with accumulation of damaged and dysfunctional mitochondria occurring early in the disease. Mitophagy, which governs mitochondrial turnover and quality control, is impaired in the AD brain, and strategies aimed at enhancing mitophagy have been identified as promising therapeutic targets. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is upregulated in AD, and ligands targeting TSPO have been shown to exert neuroprotective effects in mouse models of AD. However, whether TSPO ligands modulate mitophagy in AD has not been explored. Here, we provide evidence that the TSPO-specific ligands Ro5-4864 and XBD173 attenuate mitophagy deficits and mitochondrial fragmentation in a cellular model of AD overexpressing the human amyloid precursor protein (APP). Ro5-4864 and XBD173 appear to enhance mitophagy via modulation of the autophagic cargo receptor P62/SQSTM1, in the absence of an effect on PARK2, PINK1, or LC3 level. Taken together, these findings indicate that TSPO ligands may be promising therapeutic agents for ameliorating mitophagy deficits in AD.

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http://hdl.handle.net/10453/183940