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Yeast as a gateway to conquering protein misfolding diseases.

酵母是征服蛋白质错误折叠疾病的门户。

基本信息

批准号：
10810084
负责人：
SUSAN W LIEBMAN
金额：
$ 1.15万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

项目摘要

Abstract. Certain proteins misfold to form self-seeding prion-like aggregates associated with disease. We focus on one such protein, TDP-43, because it is the major protein associated neuronal aggregates in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia and LATE. LATE is a recently described prevalent TDP-43 proteinopathy that causes dementia that is often misdiagnosed as Alzheimer’s disease (AD). In addition, TDP-43 is found in aggregates associated with AD and Parkinson’s. Since TDP-43 forms aggregates and is toxic (inhibits growth) in yeast, a powerful approach to find therapeutic targets has been to identify yeast genes that modify TDP-43 toxicity. The relevance of the yeast model to human disease is clear because several yeast genes that modify toxicity of human misfolding disease proteins, including TDP-43, are homologs of new or known human disease risk factors. We will continue to study the genesis and toxicity of TDP-43 aggregates in yeast building on our expertise with yeast self-seeding prion proteins. We expect to learn how TDP-43 causes toxicity in yeast and in what ways this relates to TDP-43 toxicity in flies, primary cortical neurons and mice. One of our goals is to investigate the range of condensates, oligomers and aggregates formed by TDP-43 and their associated toxicities. Determining which species of TDP-43 is most toxic is an important step towards understanding of toxicity mechanisms. It is also largely unknown what cellular functions are targeted by toxic TDP-43 species and the affiliated mechanisms. We will identify and study cellular targets of toxicity focusing on TDP-43 gain of function toxicity. We will also explore new models of therapeutic approaches by investigating if overexpression of TDP-43 binding proteins can inhibit the formation of toxic TDP- 43 species, if titration of important proteins by TDP-43 toxic species contributes to toxicity, and if mutations in TDP-43 can protect WT TDP-43 expressed in the same cell from forming toxic aggregates. Another gap we seek to address is why TDP-43 is associated with different diseases. Importantly, as we showed for yeast prions, TDP-43 and other disease proteins can form distinct aggregate variants (strains), unrelated to mutation, that are associated with distinct characteristics. Thus, different variants of TDP-43 could affect neuronal types differently causing e.g. ALS vs. LATE. TDP-43 variants established in yeast would be important tools to identify disease specific variants and facilitate development of variant specific treatments. We will also investigate the idea that entry into liquid-like granules is an upstream trigger for toxic species formation to learn if liquid-like granules are therapeutic targets. We will quantify the relationship between entry of prion proteins into liquid condensates and stochastic formation of prions in yeast. We will also explore the new area of disease associated metabolite amyloid-like aggregates and the hypothesis that they nucleate prion-like/disease protein misfolding much as we showed cross-seeding between yeast prions. We hope this work will lead to new treatment approaches for protein misfolding diseases.

抽象的。某些蛋白质错误折叠，形成与疾病相关的自我播种朊病毒样聚集体。我们我们关注一种这样的蛋白质，TDP-43，因为它是与神经元相关的主要蛋白质。包括肌萎缩侧索硬化症在内的几种神经退行性疾病中的聚集体 (ALS)、额颞叶痴呆和LATE。LATE是最近描述的流行TDP-43 蛋白质病导致痴呆，常被误诊为阿尔茨海默病（AD）。在此外，TDP-43存在于与AD和帕金森病相关的聚集体中。自TDP-43以来在酵母中形成聚集体并且是有毒的（抑制生长），这是一种找到治疗方法的有效方法。目标是鉴定改变TDP-43毒性的酵母基因。酵母的相关性人类疾病的模型是明确的，因为几个酵母基因，修改人类的毒性错误折叠的疾病蛋白，包括TDP-43，是新的或已知的人类疾病的同源物危险因素我们将继续研究TDP-43聚集体在酵母中的发生和毒性基于我们在酵母自接种朊病毒蛋白方面的专业知识。我们希望了解TDP-43 在酵母中引起毒性，以及这与TDP-43在苍蝇中的毒性，初级皮质神经元和小鼠。我们的目标之一是研究冷凝物，低聚物和 TDP-43形成的聚集体及其相关毒性。确定哪些物种 TDP-43毒性最强是了解毒性机制的重要一步。是毒性TDP-43物质靶向的细胞功能在很大程度上也是未知的，附属机制。我们将确定和研究毒性的细胞靶点，重点是TDP-43 功能毒性增加。我们还将探索新的治疗方法模型，研究TDP-43结合蛋白的过表达是否可以抑制毒性TDP-43的形成， 43种，如果TDP-43毒性物质对重要蛋白质的滴定导致毒性，并且如果 TDP-43的突变可以保护在同一细胞中表达的WT TDP-43免于形成毒性集料.我们寻求解决的另一个差距是为什么TDP-43与不同的疾病重要的是，正如我们在酵母朊病毒中所展示的那样，TDP-43和其他疾病蛋白可以形成与突变无关的不同的聚合变异体（菌株），这些变异体与不同的特色因此，TDP-43的不同变体可以不同地影响神经元类型，例如ALS与LATE。在酵母中建立的TDP-43变体将是鉴定疾病特异性变体并促进变体特异性治疗的开发。我们还将调查进入液体状颗粒是有毒物质的上游触发因素的想法以了解液体状颗粒是否是治疗靶点。我们将量化朊病毒蛋白进入液体凝聚物和朊病毒在细胞中随机形成之间的关系酵母我们还将探索疾病相关代谢物淀粉样蛋白的新领域，聚集体和假设，他们核朊病毒样/疾病蛋白质错误折叠，我们发现了酵母朊病毒之间的交叉接种。我们希望这项工作能带来新的治疗方法蛋白质错误折叠疾病的方法。