Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson's disease.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-03-25 Epub Date: 2025-03-07 DOI:10.1016/j.celrep.2025.115355

Thomas P Spargo, Chloe F Sands, Isabella R Juan, Jonathan Mitchell, Vida Ravanmehr, Jessica C Butts, Ruth B De-Paula, Youngdoo Kim, Fengyuan Hu, Quanli Wang, Dimitrios Vitsios, Manik Garg, Lawrence Middleton, Michal Tyrlik, Mirko Messa, Guillermo Del Angel, Daniel G Calame, Hiba Saade, Laurie Robak, Ben Hollis, Vishnu A Cuddapah, Huda Y Zoghbi, Joshua M Shulman, Slavé Petrovski, Ismael Al-Ramahi, Ioanna Tachmazidou, Ryan S Dhindsa

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Abstract

Despite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10^-7; odds ratio [95% confidence interval] = 10.5 [5.2, 21.3]). We replicate this association in three independent datasets totaling 8,407 cases and 413,432 controls (combined p = 4.5 × 10^-12). Notably, ITSN1 haploinsufficiency has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, we find that loss of the ITSN1 ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity and motor deficits, and in vitro assays further suggest a physical interaction between ITSN1 and α-synuclein. These results firmly establish ITSN1 as a PD risk gene with an effect size exceeding previously established loci, implicate vesicular trafficking dysfunction in PD pathogenesis, and potentially open new avenues for therapeutic development.

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ITSN1单倍体缺陷与帕金森病风险显著增加相关。

尽管具有显著的遗传性，但帕金森病（PD）的遗传基础仍不完全清楚。在此，通过分析来自英国生物银行（UK Biobank）的3,809例PD病例和247,101例对照的全基因组序列数据，我们发现ITSN1的蛋白截断变异会显著增加PD的风险(p = 6.1 × 10-7；优势比[95%置信区间]= 10.5[5.2,21.3])。我们在三个独立的数据集中重复了这种关联，总共8407例病例和413432例对照（合并p = 4.5 × 10-12）。值得注意的是，ITSN1单倍不足也与自闭症谱系障碍有关，这表明外显率/表达率是可变的。在果蝇中，我们发现ITSN1同源基因Dap160的缺失加剧了α-突触核蛋白诱导的神经元毒性和运动缺陷，体外实验进一步表明ITSN1和α-突触核蛋白之间存在物理相互作用。这些结果坚定地确立了ITSN1是PD风险基因，其效应大小超过了先前确定的位点，暗示了PD发病机制中的囊泡运输功能障碍，并可能为治疗开发开辟新的途径。

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

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.