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SGIP1 中的候选功能丧失变异导致突触功能障碍和隐性帕金森病。

A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism.

机构信息

VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.

Laboratory of Molecular Biology, Sainte-Justine University Hospital Center, Montréal QC H3T 1C5, Canada.

出版信息

Cell Rep Med. 2024 Oct 15;5(10):101749. doi: 10.1016/j.xcrm.2024.101749. Epub 2024 Sep 26.

DOI:10.1016/j.xcrm.2024.101749
PMID:39332416
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11513836/
Abstract

Synaptic dysfunction is recognized as an early step in the pathophysiology of parkinsonism. Several genetic mutations affecting the integrity of synaptic proteins cause or increase the risk of developing disease. We have identified a candidate causative mutation in synaptic "SH3GL2 Interacting Protein 1" (SGIP1), linked to early-onset parkinsonism in a consanguineous Arab family. Additionally, affected siblings display intellectual, cognitive, and behavioral dysfunction. Metabolic network analysis of [F]-fluorodeoxyglucose positron emission tomography scans shows patterns very similar to those of idiopathic Parkinson's disease. We show that the identified SGIP1 mutation causes a loss of protein function, and analyses in newly created Drosophila models reveal movement defects, synaptic transmission dysfunction, and neurodegeneration, including dopaminergic synapse loss. Histology and correlative light and electron microscopy reveal the absence of synaptic multivesicular bodies and the accumulation of degradative organelles. This research delineates a putative form of recessive parkinsonism, converging on defective synaptic proteostasis and opening avenues for diagnosis, genetic counseling, and treatment.

摘要

突触功能障碍被认为是帕金森病病理生理学的早期步骤。几种影响突触蛋白完整性的基因突变导致或增加了发病风险。我们在一个近亲阿拉伯家族中发现了一个与早发性帕金森病相关的突触“SH3GL2 相互作用蛋白 1”（SGIP1）的候选致病突变。此外，受影响的兄弟姐妹还表现出智力、认知和行为功能障碍。[F]-氟脱氧葡萄糖正电子发射断层扫描的代谢网络分析显示出与特发性帕金森病非常相似的模式。我们表明，鉴定出的 SGIP1 突变导致蛋白功能丧失，并且在新创建的果蝇模型中的分析显示出运动缺陷、突触传递功能障碍和神经退行性变，包括多巴胺能突触丧失。组织学和相关的光镜和电子显微镜显示突触多泡体缺失和降解细胞器积累。这项研究描绘了一种可能的隐性帕金森病形式，其特征是突触蛋白稳态缺陷，并为诊断、遗传咨询和治疗开辟了途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/f6cd7b204323/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/a831f8b4b6f7/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/c2bb227df650/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/5deb8e18002d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/ed6b206dae00/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/67d6bbf88deb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/7262b8b29a89/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/528e012c07f9/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/f6cd7b204323/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/a831f8b4b6f7/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/c2bb227df650/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/5deb8e18002d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/ed6b206dae00/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/67d6bbf88deb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/7262b8b29a89/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/528e012c07f9/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfff/11513836/f6cd7b204323/gr7.jpg

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