Rhine_NatNeuro_2024

Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging markers. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins – like the dementia and ALS-associated protein TDP-43 – mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components typically are recruited to stress granules, but aged neurons suffer from chronic stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity, and the failure to respond to new stress events. Together our data demonstrates that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.衰老是神经退行性病变最显著的风险因素之一，但老年神经元功能退化背后的分子机制仍大多未被阐明。为高效研究衰老背景下的神经退行性过程，我们将来自健康老年供体的原代人成纤维细胞直接转分化为保留自身衰老标志物的神经元。本研究发现，老年神经元广泛缺失RNA结合蛋白（RNA-binding proteins），尤其是剪接体（spliceosome）组分。值得注意的是，剪接蛋白——如与痴呆和肌萎缩侧索硬化症（ALS）相关的TDP-43——在老年神经元中错误定位至细胞质，进而引发广泛的可变剪接异常。通常情况下，细胞质中的剪接体组分会被招募至应激颗粒（stress granules），但老年神经元处于慢性应激状态，无法完成这一隔离过程。我们将该慢性应激与功能异常的泛素化（ubiquitylation）系统、低下的HSP90α分子伴侣活性，以及无法应对新发应激事件建立了关联。综合本研究所有数据可见，与衰老相关的RNA生物学功能退化是老年神经元恢复能力低下的关键驱动因素。