Proteotoxic regulation of neurodegeneration by TIR-1/Sarm1

TIR-1/Sarm1 对神经变性的蛋白毒性调节

• 批准号: RGPIN-2016-05745
• 负责人: Parker, Alex
• 金额: $ 2.4万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=661604
• 关键词: Proteotoxic; regulation; neurodegeneration; TIR; Sarm1

Protein homeostasis (proteostasis) is essential for cellular function and survival since proteins play critical roles in nearly all cellular processes. Proteostasis refers to the global network maintaining proper synthesis, folding, modification, transport, and degradation of proteins within a cell. Proteostasis is extensively controlled during development and is essential to survival and healthy aging but gradually becomes less efficient as cells and organisms age. Proteotoxicity refers to the progressive accumulation of misfolded mutant protein products with negative consequences to cellular function and survival. We recently discovered that misfolded proteins within neurons trigger a paracrine-like innate immune response ultimately leading to neurodegeneration. Central to this mechanism is the adaptor protein TIR-1/Sarm1 which functions at the interface of immune response and axonal survival pathways. The TIR-1/Sarm1 pathway may be an ancient, conserved regulator of neurodegeneration, but the mechanisms underlying its activation under stress conditions are not known. Furthermore, it is not clear how the nervous system communicates to other tissues to activate an immune response. In our fundamental research program, we will address these biological questions by exploiting the model organism C. elegans to investigate the genetic and molecular pathways governed by TIR-1 in regulating the survival of neurons under conditions of proteotoxic stress. Specifically we will attempt to identify the signalling molecules originating in neurons that activate an organism-wide immune response, and we will construct a genetic pathway for TIR-1/Sarm1 in regulating neuronal survival.**

蛋白质稳态（proteostasis）对于细胞功能和存活是必不可少的，因为蛋白质在几乎所有细胞过程中起关键作用。蛋白质稳态是指维持细胞内蛋白质的适当合成、折叠、修饰、运输和降解的全球网络。蛋白质稳态在发育过程中受到广泛控制，对生存和健康衰老至关重要，但随着细胞和生物体的衰老，蛋白质稳态的效率逐渐降低。蛋白毒性是指错误折叠的突变蛋白产物的进行性积累，对细胞功能和存活具有负面影响。我们最近发现，神经元内的错误折叠蛋白质会触发类似旁分泌的先天免疫反应，最终导致神经退行性变。该机制的核心是衔接蛋白TIR-1/Sarm 1，其在免疫应答和轴突存活途径的界面处起作用。TIR-1/Sarm 1通路可能是一种古老的、保守的神经变性调节因子，但其在应激条件下激活的机制尚不清楚。此外，目前尚不清楚神经系统如何与其他组织沟通以激活免疫反应。在我们的基础研究计划中，我们将通过利用模式生物C来解决这些生物学问题。elegans研究TIR-1在蛋白毒性应激条件下调节神经元存活的遗传和分子途径。具体来说，我们将尝试识别源自神经元的信号分子，这些信号分子激活生物体范围的免疫反应，我们将构建TIR-1/Sarm 1调节神经元存活的遗传途径。