帕金森氏症风险变体会损害突触自噬诱导的嗜内蛋白-A/SH3GL2钙离子开关。

IF 14.6 1区 生物学 Q1 CELL BIOLOGY
Autophagy Pub Date : 2024-04-01 Epub Date: 2023-04-17 DOI:10.1080/15548627.2023.2200627
Marianna Decet, Sandra-Fausia Soukup
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引用次数: 0

摘要

在突触中,蛋白质在神经元活动过程中会被多次重复使用,从而导致蛋白质功能随着时间的推移而下降。尽管新的证据支持自噬在突触功能中的作用,但连接神经元活动、自噬和突触功能障碍的确切分子机制却鲜为人知。我们展示了突触前末端的细胞外钙流入如何构成自噬体形成的最初刺激,以应对神经元活动。当神经元的剧烈活动对突触蛋白质组提出挑战时,这种机制可能会迅速支持突触的平衡和蛋白质质量控制。我们确定了 EndoA(嗜内蛋白 A)柔性区域中的一个残基,该残基决定了钙依赖性 EndoA 从质膜到细胞质的移动,在细胞质中,该蛋白与自噬膜相互作用,促进自噬体的形成。我们发现,SH3GL2(SH3 domain containing GRB2 like 2,endophilin A1)中的一种新型帕金森病风险突变破坏了 SH3GL2 的钙传感功能,导致蛋白无法移动,无法对钙流入做出反应,从而破坏了突触处的自噬诱导。我们的工作表明了神经元活动如何与自噬联系在一起,以维持突触的平衡和存活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Endophilin-A/SH3GL2 calcium switch for synaptic autophagy induction is impaired by a Parkinson's risk variant.

At the synapse, proteins are reused several times during neuronal activity, causing a decline in protein function over time. Although emerging evidence supports a role of autophagy in synaptic function, the precise molecular mechanisms linking neuronal activity, autophagy and synaptic dysfunction are vastly unknown. We show how extracellular calcium influx in the pre-synaptic terminal constitutes the initial stimulus for autophagosome formation in response to neuronal activity. This mechanism likely acts to rapidly support synaptic homeostasis and protein quality control when intense neuronal activity challenges the synaptic proteome. We identified a residue in the flexible region of EndoA (Endophilin A) that dictates calcium-dependent EndoA mobility from the plasma membrane to the cytosol, where this protein interacts with autophagic membranes to promote autophagosome formation. We discovered that a novel Parkinson's disease-risk mutation in SH3GL2 (SH3 domain containing GRB2 like 2, endophilin A1) disrupts the calcium sensing of SH3GL2, leading to an immobile protein that cannot respond to calcium influx and therefore disrupting autophagy induction at synapses. Our work shows how neuronal activity is connected with autophagy to maintain synaptic homeostasis and survival.

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来源期刊
Autophagy
Autophagy 生物-细胞生物学
CiteScore
21.30
自引率
2.30%
发文量
277
审稿时长
1 months
期刊介绍: Autophagy is a peer-reviewed journal that publishes research on autophagic processes, including the lysosome/vacuole dependent degradation of intracellular material. It aims to be the premier journal in the field and covers various connections between autophagy and human health and disease, such as cancer, neurodegeneration, aging, diabetes, myopathies, and heart disease. Autophagy is interested in all experimental systems, from yeast to human. Suggestions for specialized topics are welcome. The journal accepts the following types of articles: Original research, Reviews, Technical papers, Brief Reports, Addenda, Letters to the Editor, Commentaries and Views, and Articles on science and art. Autophagy is abstracted/indexed in Adis International Ltd (Reactions Weekly), EBSCOhost (Biological Abstracts), Elsevier BV (EMBASE and Scopus), PubMed, Biological Abstracts, Science Citation Index Expanded, Web of Science, and MEDLINE.
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