Podvin Sonia, Rosenthal Brin, Mosier Charles, Wei Enlin, Fisch Kathleen M, Hook Vivian
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
J Huntingtons Dis. 2025 Jul 23:18796397251358348. doi: 10.1177/18796397251358348.
BackgroundHuman Huntington's disease (HD) is a genetic neurodegenerative disorder caused by the mutant gene containing CAG repeat expansions, resulting in motor dysfunction and behavioral deficits. CAG repeats of 40-53 occur in adult HD and 60-120 repeats occur in early onset juvenile HD, differing from the normal range of 5-35 repeats.ObjectiveThe gene is translated to the huntingtin (HTT) protein that interacts with proteins in the development of HD. There have been few studies of HTT protein interactors in human HD brain. Therefore, this study evaluated the hypothesis that dysregulation of HTT protein interactors occurs in human juvenile HD brains.MethodsThe strategy of this study was to analyze proteomic data of human juvenile HD brain putamen and cortex regions for dysregulation of HTT interacting proteins, using a database that we compiled of HTT interactors identified in HD model systems from yeast to HD mice.ResultsResults showed significant dysregulation of HTT protein interactors of mitochondria, signal transduction, RNA splicing, chromatin organization, translation, membrane trafficking, endocytosis, vesicle, protein modification, granule membrane, and macroautophagy pathways. The majority of downregulated and upregulated HTT interactors occurred in the putamen region compared to cortex. Dysregulation displayed downregulation of mitochondria and signal transduction interactors, combined with upregulation of RNA splicing, chromatin organization, and translational interactors. Network analysis revealed interactions among clusters of HTT interactors.ConclusionsThese findings demonstrate prevalent dysregulation of HTT protein interactors in human juvenile HD brain, especially in the putamen region that controls movement deficits in HD.
背景
人类亨廷顿舞蹈症（HD）是一种由含有CAG重复序列扩增的突变基因引起的遗传性神经退行性疾病，会导致运动功能障碍和行为缺陷。成人HD中CAG重复序列为40 - 53个，早发性青少年HD中CAG重复序列为60 - 120个，不同于正常范围的5 - 35个重复序列。
目的
该基因翻译为亨廷顿蛋白（HTT），其在HD的发生发展过程中与多种蛋白质相互作用。目前针对人类HD大脑中HTT蛋白相互作用分子的研究较少。因此，本研究评估了人类青少年HD大脑中HTT蛋白相互作用分子失调的假说。
方法
本研究的策略是利用我们编制的一个数据库，该数据库包含从酵母到HD小鼠等HD模型系统中鉴定出的HTT相互作用分子，分析人类青少年HD大脑壳核和皮质区域的蛋白质组学数据，以确定HTT相互作用蛋白的失调情况。
结果
结果显示，线粒体、信号转导、RNA剪接、染色质组织、翻译、膜运输、内吞作用、囊泡、蛋白质修饰、颗粒膜和巨自噬途径的HTT蛋白相互作用分子存在显著失调。与皮质相比，大多数下调和上调的HTT相互作用分子出现在壳核区域。失调表现为线粒体和信号转导相互作用分子的下调，同时伴有RNA剪接、染色质组织和翻译相互作用分子的上调。网络分析揭示了HTT相互作用分子簇之间的相互作用。
结论
这些发现表明，人类青少年HD大脑中HTT蛋白相互作用分子普遍失调，尤其是在控制HD运动缺陷的壳核区域。
