Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer's Disease Relevant Tau Modification in a Novel C. elegans Model.

IF 3.3 3区 生物学 Genetics Pub Date : 2021-11-29 DOI:10.21203/rs.3.rs-1096882/v1
Sanjib Guha, Anson Cheng, Trae Carroll, Dennisha King, Shon Koren, Sierra Swords, Keith Nehrke, Gail V W Johnson
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引用次数: 1

Abstract

Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles (NFT) is a defining feature of Alzheimer's disease (AD), with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in C. elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome (ML) morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator Drp1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to AD pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and ML neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for Drp1-independent, Pink1-dependent, perhaps adaptive, mitophagy.
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在一种新的秀丽隐杆线虫模型中,与阿尔茨海默病相关的Tau修饰选择性地破坏了drp1独立的有丝分裂和有丝分裂酶体运输。
不适当磷酸化的tau积累到神经原纤维缠结(NFT)中是阿尔茨海默病(AD)的一个决定性特征,tau pT231是tau病理学的早期预兆。此前,我们证明在秀丽隐杆线虫中表达人类拟磷酸突变体tau(T231E)的单个基因组拷贝会驱动年龄依赖性神经退行性变。一个关键的发现是,与野生型tau不同,T231E完全选择性地抑制了氧化应激诱导的线粒体自噬。在这里,我们使用动态成像方法来分析线粒体和线粒体溶酶体(ML)形态、丰度、运输和应激诱导的线粒体自噬的T231E相关变化,作为线粒体分裂介质Drp1的功能,Drp1已被证明与高磷酸化的tau相互作用,并有助于AD的发病机制,一种公认的线粒体质量控制介质,与Parkin一起支持应激诱导的线粒体自噬。T231E以优异的选择性影响线粒体自噬和ML轴突运输,避免了大自噬以及溶酶体和自溶体运输。氧化应激诱导的线粒体自噬和T231E抑制线粒体自噬的能力都独立于drp-1,但至少部分依赖于pink-1。细胞器运输更为复杂,drp-1和pink-1突变体发挥独立作用,但通常支持线粒体自噬表型在T231E中具有更大生理影响的观点。总之,我们的研究结果完善了T231E导致神经退行性变的机制途径,证明了对模拟tau病相关翻译后修饰的突变的病理选择性,对含有受损线粒体的细胞器的生理选择性,以及对Drp1非依赖性、Pink1依赖性、可能是适应性的线粒体自噬的分子选择性。
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来源期刊
Genetics
Genetics 生物-遗传学
CiteScore
6.20
自引率
6.10%
发文量
177
期刊介绍: GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.
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