pH modulation restores proteostasis and extend lifespan in a yeast model of Huntington’s Disease [pH]

Loss of proteostasis is a hallmark of the aging process and is associated with the onset of several neurodegenerative diseases, including Huntington’s Disease (HD) where aberrant polyglutamine (polyQ) expanded Huntingtin aggregates into insoluble inclusions bodies (IBs) associated with toxicity in neuronal cells. In yeast, chronological lifespan (CLS) assays are used to model aging of non-dividing cells such as neurons. During CLS, acidification of the culture media due accumulation of acetic acid is one of the major cell extrinsic factors responsible for cell death. Thus, buffering media pH to prevent acidification significantly extends longevity. Here, we found that cells expressing pathogenic polyQ expansions display increased sensitivity to acetic acid and shortened CLS. Buffering media pH promotes both polyQ aggregation into IBs and longevity. We found that growth at higher pH induces the activation of heat shock response (HSR) in young cells. Such hormetic HSR activation subsequently allowed aged cells to mount a proper HSR in response to stresses such as heat shock or polyQ misfolding, leading to lifespan extension. Thus, our study provides new insight into how pH can promote proteotoxic stress resistance and longevity.蛋白质稳态（proteostasis）丧失是衰老进程的标志性特征，且与多种神经退行性疾病的发病密切相关。以亨廷顿病（Huntington’s Disease, HD）为例，患者体内异常扩增的聚谷氨酰胺（polyglutamine, polyQ）会促使亨廷顿蛋白聚集形成不溶性包涵体（insoluble inclusions bodies, IBs），并与神经元细胞的毒性效应相关。在酵母研究体系中，时序寿命（chronological lifespan, CLS）检测常被用于模拟神经元等非分裂细胞的衰老过程。在CLS实验周期内，因乙酸积累导致培养基酸化，是引发细胞死亡的主要细胞外源性因素之一。因此，通过缓冲培养基pH值以抑制酸化，可显著延长细胞寿命。本研究发现，表达致病性聚谷氨酰胺扩增产物的细胞对乙酸的敏感性显著升高，且时序寿命缩短。缓冲培养基pH值既可促进聚谷氨酰胺聚集形成不溶性包涵体，同时又能延长细胞寿命。我们还观察到，在较高pH环境下培养可激活年轻细胞的热休克反应（heat shock response, HSR）。这种具有毒物兴奋效应的热休克反应激活，后续可使衰老细胞在应对热休克或聚谷氨酰胺错误折叠等应激时，能够启动正常的热休克反应，进而实现寿命延长。综上，本研究为pH调控如何促进蛋白毒性应激抗性与细胞寿命延长提供了全新的研究视角。