Proteotoxic regulation of neurodegeneration by TIR-1/Sarm1

蛋白质稳态对细胞功能和生存至关重要，因为蛋白质在几乎所有的细胞过程中都起着关键作用。蛋白质平衡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。蛋白质平衡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老化，其效率逐渐降低。蛋白质毒性是指错误折叠的突变蛋白产物逐渐积累，对细胞功能和生存产生负面影响。我们最近发现，神经元内错误折叠的蛋白质会触发旁分泌的先天免疫反应，最终导致神经退化。该机制的核心是接头蛋白TIR-1/Sarm1，它在免疫反应和轴突存活途径的界面上发挥作用。TIR-1/Sarm1通路可能是一种古老的、保守的神经退行性变调节因子，但其在应激条件下激活的机制尚不清楚。此外，目前还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秀丽线虫来研究TIR-1在蛋白毒性应激条件下调控神经元存活的遗传和分子途径来解决这些生物学问题。具体地说，我们将试图确定起源于神经元的信号分子，这些分子激活了整个生物体的免疫反应，并将为TIR-1/Sarm1在调节神经元生存中构建一条遗传途径。

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.