近日，美国阿尔伯特·爱因斯坦医学院Ana Maria Cuervo及其团队发现了伴侣介导的自噬通过突触蛋白质组的性别特异性重塑来调节神经元活动。该项研究成果发表在2025年10月14日出版的《自然—细胞生物学》上。

本研究表明，CMA缺乏症会引起神经元亢进、癫痫易感性增加和钙稳态破坏。CMA缺乏的雌性突触前神经递质释放和NMDA受体介导的传递增强，而雄性突触后AMPA受体活性升高。比较定量蛋白质组学显示，CMA降解的突触蛋白存在性别二态性，雌性突触前蛋白质组优先重构，雄性突触后蛋白质组优先重构。该团队证明，在老年小鼠和阿尔茨海默病模型中，遗传或药理学激活CMA可以恢复突触蛋白水平，降低神经元的高兴奋性和癫痫易感性，并使神经传递正常化。他们的发现揭示了CMA在调节神经元兴奋性中的作用，并强调了这一途径作为减轻与年龄相关的神经元衰退的潜在目标。

研究人员表示，伴侣介导的自噬（CMA）在衰老和神经退行性疾病中下降。神经元中CMA的缺失导致小鼠神经退行性变和行为改变，但CMA在神经元生理学中的作用在很大程度上是未知的。

附：英文原文

Title: Chaperone-mediated autophagy regulates neuronal activity by sex-specific remodelling of the synaptic proteome

Author: Khawaja, Rabia R., Griego, Ernesto, Lindenau, Kristen, Salek, Asma, Gambardella, Jessica, Scrivo, Aurora, Monday, Hannah R., Bourdenx, Mathieu, Madero-Prez, Jess, Khan, Zohaib N., Chavda, Bhakti, Cutler, Ronald, Graff, Sarah, Sidoli, Simone, Santulli, Gaetano, Santambrogio, Laura, Tasset, Inmaculada, Kaushik, Susmita, Gan, Li, Castillo, Pablo E., Cuervo, Ana Maria

Issue&Volume: 2025-10-14

Abstract: Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males exhibited elevated post-synaptic AMPA-receptor activity. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodelling of the pre-synaptic proteome in females and the post-synaptic proteome in males. We demonstrate that genetic or pharmacological CMA activation in old mice and an Alzheimer’s disease mouse model restores synaptic protein levels, reduces neuronal hyperexcitability and seizure susceptibility, and normalizes neurotransmission. Our findings unveil a role for CMA in regulating neuronal excitability and highlight this pathway as a potential target for mitigating age-related neuronal decline.

DOI: 10.1038/s41556-025-01771-1

Source: https://www.nature.com/articles/s41556-025-01771-1