UBL3 Interacts with PolyQ-Expanded Huntingtin Fragments and Modifies Their Intracellular Sorting.

IF 3.2 Q2 CLINICAL NEUROLOGY Neurology International Pub Date : 2024-10-22 DOI:10.3390/neurolint16060089
Soho Oyama, Hengsen Zhang, Rafia Ferdous, Yuna Tomochika, Bin Chen, Shuyun Jiang, Md Shoriful Islam, Md Mahmudul Hasan, Qing Zhai, A S M Waliullah, Yashuang Ping, Jing Yan, Mst Afsana Mimi, Chi Zhang, Shuhei Aramaki, Yusuke Takanashi, Tomoaki Kahyo, Yoshio Hashizume, Daita Kaneda, Mitsutoshi Setou
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Abstract

Background/objectives: UBL3 (Ubiquitin-like 3) is a protein that plays a crucial role in post-translational modifications, particularly in regulating protein transport within small extracellular vesicles. While previous research has predominantly focused on its interactions with α-synuclein, this study investigates UBL3's role in Huntington's disease (HD). HD is characterized by movement disorders and cognitive impairments, with its pathogenesis linked to toxic, polyglutamine (polyQ)-expanded mutant huntingtin fragments (mHTT). However, the mechanisms underlying the interaction between UBL3 and mHTT remain poorly understood.

Methods: To elucidate this relationship, we performed hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) on postmortem brain tissue from HD patients. Gaussia princeps-based split-luciferase complementation assay and co-immunoprecipitation were employed to confirm the interaction between UBL3 and mHTT. Additionally, we conducted a HiBiT lytic detection assay to assess the influence of UBL3 on the intracellular sorting of mHTT. Finally, immunocytochemical staining was utilized to validate the colocalization and distribution of these proteins.

Results: Our findings revealed UBL3-positive inclusions in the cytoplasm and nuclei of neurons throughout the striatum of HD patients. We discovered that UBL3 colocalizes and interacts with mHTT and modulates its intracellular sorting.

Conclusions: These results suggest that UBL3 may play a significant role in the interaction and sorting of mHTT, contributing to the understanding of its potential implications in the pathophysiology of Huntington's disease.

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UBL3 与 PolyQ 扩增的亨廷汀片段相互作用并改变它们的胞内排序
背景/目的:UBL3(类泛素 3)是一种在翻译后修饰中发挥关键作用的蛋白质,尤其是在调节蛋白质在细胞外小囊泡内的转运方面。以往的研究主要集中在它与α-突触核蛋白的相互作用上,而本研究则调查了UBL3在亨廷顿氏病(HD)中的作用。HD以运动障碍和认知障碍为特征,其发病机制与有毒的多谷氨酰胺(polyQ)扩增突变亨廷汀蛋白片段(mHTT)有关。然而,人们对UBL3和mHTT之间的相互作用机制仍然知之甚少:为了阐明这种关系,我们对 HD 患者的死后脑组织进行了苏木精和伊红(HE)染色和免疫组化(IHC)。为了证实 UBL3 与 mHTT 之间的相互作用,我们采用了基于高斯太子的分裂荧光素酶互补试验和共免疫沉淀。此外,我们还进行了HiBiT裂解检测试验,以评估UBL3对mHTT胞内分选的影响。最后,我们利用免疫细胞化学染色法验证了这些蛋白的共定位和分布:我们的研究结果表明,UBL3 阳性包涵体存在于 HD 患者整个纹状体的神经元细胞质和细胞核中。我们发现UBL3与mHTT共定位和相互作用,并调节其胞内排序:这些结果表明,UBL3可能在mHTT的相互作用和分选中发挥了重要作用,有助于人们了解其在亨廷顿氏病的病理生理学中的潜在影响。
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来源期刊
Neurology International
Neurology International CLINICAL NEUROLOGY-
CiteScore
3.70
自引率
3.30%
发文量
69
审稿时长
11 weeks
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