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

被引:5
作者
Fairley, Lauren H. [1 ]
Grimm, Amandine [1 ,2 ]
Herff, Steffen A. [3 ]
Eckert, Anne [1 ,2 ]
机构
[1] Univ Basel, Neurobiol Lab Brain Aging & Mental Hlth, Res Cluster Mol & Cognit Neurosci, Basel, Switzerland
[2] Psychiat Univ Clin, Basel, Switzerland
[3] Western Sydney Univ, MARCS Inst Brain Behav & Dev, Penrith, Australia
基金
瑞士国家科学基金会;
关键词
Mitophagy; Alzheimer's disease; TSPO; Amyloid; Translocator protein; Autophagy; Mitochondria;
D O I
10.1016/j.biochi.2024.01.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (c) 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
引用
收藏
页码:132 / 138
页数:7
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