Distinct sets of lysosomal genes define synucleinopathy and tauopathy.

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
BMB Reports Pub Date : 2023-12-01
Kyu Won Oh, Dong-Kyu Kim, Ao-Lin Hsu, Seung-Jae Lee
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Abstract

Neurodegenerative diseases are characterized by distinct protein aggregates, such as those of α-synuclein and tau. Lysosomal defect is a key contributor to the accumulation and propagation of aberrant protein aggregates in these diseases. The discoveries of common proteinopathies in multiple forms of lysosomal storage diseases (LSDs) and the identification of some LSD genes as susceptible genes for those proteinopathies suggest causative links between LSDs and the proteinopathies. The present study hypothesized that defects in lysosomal genes will differentially affect the propagation of α-synuclein and tau proteins, thereby determining the progression of a specific proteinopathy. We established an imaging-based high-contents screening (HCS) system in Caenorhabditis elegans (C. elegans) model, by which the propagation of α-synuclein or tau is measured by fluorescence intensity. Using this system, we performed RNA interference (RNAi) screening to induce a wide range of lysosomal malfunction through knock down of 79 LSD genes, and to obtain the candidate genes with significant change in protein propagation. While some LSD genes commonly affected both α-synuclein and tau propagation, our study identified the distinct sets of LSD genes that differentially regulate the propagation of either α-synuclein or tau. The specificity and efficacy of these LSD genes were retained in the disease-related phenotypes, such as pharyngeal pumping behavior and life span. This study suggests that distinct lysosomal genes differentially regulate the propagation of α-synuclein and tau, and offer a steppingstone to understanding disease specificity. [BMB Reports 2023; 56(12): 657-662].

溶酶体基因的不同集合定义了突触核蛋白病和tau病。
神经退行性疾病的特征是不同的蛋白质聚集体,如α-突触核蛋白和tau。在这些疾病中,溶酶体缺陷是异常蛋白质聚集体积累和繁殖的关键因素。在多种形式的溶酶体储存性疾病(LSD)中发现了常见的蛋白质疾病,并将一些LSD基因鉴定为这些蛋白质疾病的易感基因,这表明LSD与蛋白质疾病之间存在致病联系。本研究假设溶酶体基因的缺陷会不同地影响α-突触核蛋白和tau蛋白的繁殖,从而决定特定蛋白质疾病的进展。我们在秀丽隐杆线虫(C.elegans)模型中建立了一个基于成像的高含量筛选(HCS)系统,通过荧光强度测量α-突触核蛋白或tau的传播。使用该系统,我们进行了RNA干扰(RNAi)筛选,通过敲低79个LSD基因来诱导广泛的溶酶体功能障碍,并获得蛋白质繁殖发生显著变化的候选基因。虽然一些LSD基因通常影响α-突触核蛋白和tau的繁殖,但我们的研究确定了不同的LSD基因组,它们不同地调节α-突触蛋白或tau的传播。这些LSD基因的特异性和有效性保留在与疾病相关的表型中,如咽泵送行为和寿命。这项研究表明,不同的溶酶体基因不同地调节α-突触核蛋白和tau的繁殖,并为理解疾病特异性提供了一个跳板。
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
BMB Reports
BMB Reports 生物-生化与分子生物学
CiteScore
5.10
自引率
7.90%
发文量
141
审稿时长
1 months
期刊介绍: The BMB Reports (BMB Rep, established in 1968) is published at the end of every month by Korean Society for Biochemistry and Molecular Biology. Copyright is reserved by the Society. The journal publishes short articles and mini reviews. We expect that the BMB Reports will deliver the new scientific findings and knowledge to our readers in fast and timely manner.
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