Elucidation of Site-Specific Ubiquitination on Chaperones in Response to Mutant Huntingtin

IF 3.6 4区 医学 Q3 CELL BIOLOGY Cellular and Molecular Neurobiology Pub Date : 2023-12-15 DOI:10.1007/s10571-023-01446-1
Prajnadipta Panda, Vivek Sarohi, Trayambak Basak, Prasad Kasturi
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Abstract

Huntington's disease (HD) is one of the prominent neurodegenerative diseases, characterized by the progressive decline of neuronal function, due to the accumulation and aggregation of misfolded proteins. Pathological progression of HD is hallmarked by the aberrant aggregation of the huntingtin protein (HTT) and subsequent neurotoxicity. Molecular chaperones (heat shock proteins, HSPs) play a pivotal role in maintaining proteostasis by facilitating protein refolding, degradation, or sequestration to limit the accumulation of misfolded proteins during neurotoxicity. However, the role of post-translational modifications such as ubiquitination among HSPs during HD is less known. In this study, we aimed to elucidate HSPs ubiquitin code in the context of HD pathogenesis. In a comprehensive proteomic analysis, we identified site-specific ubiquitination events in HSPs associated with HTT in HD-affected brain regions. To assess the impact of ubiquitination on HSPs during HD, we quantified the abundance of ubiquitinated lysine sites in both the rat cortex/striatum and in the mouse primary cortical neurons. Strikingly, we observed highly tissue-specific alterations in the relative ubiquitination levels of HSPs under HD conditions, emphasizing the importance of spatial perturbed post-translational modifications (PTMs) in shaping disease pathology. These ubiquitination events, combined with other PTMs on HSPs, are likely to influence the phase transitions of HTT. In conclusion, our study uncovered differential site-specific ubiquitination of molecular chaperones and offers a comprehensive view of the intricate relationship between protein aggregation, and PTMs in the context of Huntington's disease.

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阐明伴侣蛋白在突变型亨廷廷蛋白作用下的特异性泛素化位点
亨廷顿氏病(Huntington's disease,HD)是突出的神经退行性疾病之一,其特征是由于错误折叠蛋白的积累和聚集导致神经元功能逐渐衰退。亨廷蛋白(HTT)的异常聚集和随后的神经毒性是HD病理进展的特征。分子伴侣(热休克蛋白,HSPs)通过促进蛋白质重折叠、降解或螯合来限制神经毒性过程中错误折叠蛋白质的积累,从而在维持蛋白质稳态方面发挥关键作用。然而,HSPs 在 HD 期间的翻译后修饰(如泛素化)作用却鲜为人知。在本研究中,我们旨在阐明 HD 发病过程中的 HSP 泛素密码。在一项全面的蛋白质组学分析中,我们发现了在受HD影响的大脑区域中与HTT相关的HSPs的特定位点泛素化事件。为了评估泛素化对HD过程中HSP的影响,我们对大鼠皮质/纹状体和小鼠原发性皮质神经元中泛素化赖氨酸位点的丰度进行了量化。令人震惊的是,我们观察到在 HD 条件下 HSPs 的相对泛素化水平发生了高度组织特异性的改变,这强调了空间扰动翻译后修饰 (PTM) 在形成疾病病理学中的重要性。这些泛素化事件与 HSPs 上的其他 PTMs 相结合,可能会影响 HTT 的相变。总之,我们的研究发现了分子伴侣的不同位点特异性泛素化,为亨廷顿氏病中蛋白质聚集和 PTM 之间错综复杂的关系提供了一个全面的视角。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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