加州大学Gene W. Yeo课题组揭示了神经元老化导致剪接蛋白的错误定位和不受控制的细胞应激。2025年6月2日出版的《自然—神经科学》杂志发表了这项成果。

为了有效地研究衰老背景下的神经退行性变，研究小组将来自老年健康供体的原代人成纤维细胞直接转分化为神经元，使其保留了衰老特征，并验证了在老年人和非主题脑组织中的关键发现。

在这里，小组发现衰老的神经元广泛地耗尽了RNA结合蛋白，特别是剪接体成分。有趣的是，剪接蛋白，如痴呆和ALS相关蛋白TDP-43，在衰老神经元中错误定位到细胞质，这导致了广泛的选择性剪接。细胞质剪接体成分通常被招募到应激颗粒中，但衰老的神经元受到慢性细胞应激的影响，阻止了这种隔离。研究团队将慢性应激与泛素化机制的故障、HSP90α伴侣活性低下以及对新应激事件的反应失败联系起来。总之，他们的数据表明，与衰老相关的RNA生物学退化是衰老神经元恢复能力差的关键驱动因素。

据了解，衰老是神经退行性疾病最重要的危险因素之一，但衰老神经元退化的分子机制尚不清楚。

附：英文原文

Title: Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress

Author: Rhine, Kevin, Li, Rachel, Kopalle, Hema M., Rothamel, Katherine, Ge, Xuezhen, Epstein, Elle, Mizrahi, Orel, Madrigal, Assael A., Her, Hsuan-Lin, Gomberg, Trent A., Hermann, Anita, Schwartz, Joshua L., Daniels, Amanda J., Manor, Uri, Ravits, John, Signer, Robert A. J., Bennett, Eric J., Yeo, Gene W.

Issue&Volume: 2025-06-02

Abstract: 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 hallmarks, and we verified key findings in aged human and mouse brain tissue. 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 are typically recruited to stress granules, but aged neurons suffer from chronic cellular 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 demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.

DOI: 10.1038/s41593-025-01952-z

Source: https://www.nature.com/articles/s41593-025-01952-z