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

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

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.

转运蛋白(TSPO)配体通过自噬适配体 P62 减轻阿尔茨海默病 SH-SY5Y 细胞模型中的有丝分裂缺陷。
线粒体功能障碍已被广泛认为与阿尔茨海默病(AD)的发病机制有关,受损和功能障碍线粒体的积累发生在疾病早期。线粒体吞噬是线粒体周转和质量控制的关键,在阿尔茨海默病大脑中受到损害,旨在增强线粒体吞噬的策略已被确定为有希望的治疗靶点。转运蛋白(TSPO)是一种线粒体外膜蛋白,在AD中上调,靶向TSPO的配体已被证明在AD小鼠模型中具有神经保护作用。然而,TSPO配体是否会调节AD中的有丝分裂尚未得到探讨。在这里,我们提供的证据表明,在过表达人淀粉样前体蛋白(APP)的AD细胞模型中,TSPO特异性配体Ro5-4864和XBD173可减轻有丝分裂缺陷和线粒体破碎。Ro5-4864和XBD173似乎通过调节自噬货物受体P62/SQSTM1来增强有丝分裂,而对PARK2、PINK1或LC3水平没有影响。综上所述,这些研究结果表明,TSPO 配体可能是一种很有前景的治疗药物,可用于改善 AD 的有丝分裂缺陷。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biochimie
Biochimie 生物-生化与分子生物学
CiteScore
7.20
自引率
2.60%
发文量
219
审稿时长
40 days
期刊介绍: Biochimie publishes original research articles, short communications, review articles, graphical reviews, mini-reviews, and hypotheses in the broad areas of biology, including biochemistry, enzymology, molecular and cell biology, metabolic regulation, genetics, immunology, microbiology, structural biology, genomics, proteomics, and molecular mechanisms of disease. Biochimie publishes exclusively in English. Articles are subject to peer review, and must satisfy the requirements of originality, high scientific integrity and general interest to a broad range of readers. Submissions that are judged to be of sound scientific and technical quality but do not fully satisfy the requirements for publication in Biochimie may benefit from a transfer service to a more suitable journal within the same subject area.
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