Combining light-induced aggregation and biotin proximity labeling implicates endolysosomal proteins in early α-synuclein oligomerization

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-06-06 DOI:10.1016/j.isci.2025.112823

Maxime Teixeira , Razan Sheta , Dylan Musiol , Vetso Ranjakasoa , Jérémy Loehr , Jean-Philippe Lambert , Abid Oueslati

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引用次数: 0

Abstract

Alpha-synuclein (α-syn) aggregation is a defining feature of Parkinson’s disease (PD) and related synucleinopathies. Despite significant research efforts focused on understanding α-syn aggregation mechanisms, the early stages of this process remain elusive, largely due to limitations in experimental tools that lack the temporal resolution to capture these dynamic events. Here, we introduce UltraID-LIPA, an innovative platform that combines the light-inducible protein aggregation (LIPA) system with the UltraID proximity-dependent biotinylation assay to identify α-syn-interacting proteins and uncover key mechanisms driving its oligomerization. UltraID-LIPA successfully identified 38 α-syn-interacting proteins, including both established and previously unreported candidates, highlighting the accuracy and robustness of the approach. Notably, a strong interaction with endolysosomal and membrane-associated proteins was observed, supporting the hypothesis that interactions with membrane-bound organelles are pivotal in the early stages of α-syn aggregation. This powerful platform provides new insights into dynamic protein aggregation events, enhancing our understanding of synucleinopathies and other proteinopathies.

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结合光诱导聚集和生物素接近标记涉及早期α-突触核蛋白寡聚的内溶酶体蛋白

α-突触核蛋白（α-syn）聚集是帕金森病（PD）和相关突触核蛋白病的一个决定性特征。尽管大量的研究工作集中在理解α-syn聚集机制上，但这一过程的早期阶段仍然难以捉摸，这主要是由于实验工具的限制，缺乏捕捉这些动态事件的时间分辨率。在这里，我们介绍了UltraID-LIPA，这是一个创新的平台，结合了光诱导蛋白聚集（LIPA）系统和UltraID接近依赖的生物素化测定，以识别α-syn相互作用的蛋白质，并揭示其寡聚化的关键机制。UltraID-LIPA成功鉴定了38种α-syn相互作用蛋白，包括已建立的和以前未报道的候选蛋白，突出了该方法的准确性和稳健性。值得注意的是，观察到与内溶酶体和膜相关蛋白的强相互作用，支持了与膜结合细胞器的相互作用在α-syn聚集的早期阶段至关重要的假设。这个强大的平台为动态蛋白质聚集事件提供了新的见解，增强了我们对突触核蛋白病和其他蛋白质病的理解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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