感染和除草剂暴露与c-Abl激酶α-Synuclein Ser129磷酸化有关。

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Marzieh Ehsani, Zeyang Sun, Alvaro Quevedo-Olmos, Gesa Rösler, Mahdi Rasa, Anca Kliesow Remes, Nina Hedemann, Oliver J Müller, Saskia F Erttmann, David Holthaus, Thomas F Meyer
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引用次数: 0

摘要

背景:帕金森病是一种复杂的、多因素的神经退行性疾病,其特征是α-突触核蛋白聚集到路易小体中,丝氨酸129 (pSer129)的磷酸化是关键的调控位点和病理标志。然而,环境触发因素导致这种疾病表型的确切机制仍然知之甚少。在这项研究中,我们研究了具有代表性的感染和农药暴露对pSer129 α-突触核蛋白的影响,特别关注细胞激酶在介导这一过程中的作用。方法:神经细胞暴露于两种不同的环境应激源:农药鱼藤酮和已知的胃幽门螺杆菌(H. pylori)。免疫荧光染色或Western blot检测血清Ser129 α-突触核蛋白磷酸化水平及线粒体损伤程度。为了研究c-Abl的作用,用不同机制的c-Abl抑制剂和siRNA处理细胞。Western blotting检测pSer129 α-Synuclein的水平,通过激酶谱分析预测上游丝氨酸/苏氨酸激酶的活性,并通过Western blotting验证。此外,对处理细胞进行转录组分析,并应用独创性途径分析和DESeq2来识别受感染/治疗影响的神经退行性途径。结果:我们的rna测序数据的功能分析显示,幽门螺杆菌和鱼藤酮都诱导神经炎症和细胞应激反应途径。尽管它们可能通过不同的上游介质激活c-Abl,但两者最终都促进α-突触核蛋白磷酸化。用c-Abl抑制剂Ponatinib和Asciminib治疗可有效阻止pSer129 α-synuclein的积累,逆转H. pylori或鱼藤酮诱导的相关基因表达变化。此外,GSK3β已被确定为激活c-Abl信号下游发生的Ser129磷酸化的贡献者。值得注意的是,幽门螺杆菌产生的空泡细胞毒素(VacA)似乎在c- abl介导的α-突触核蛋白Ser129磷酸化中起关键作用。结论:这些发现突出了c-Abl在α-突触核蛋白病中的关键作用,并为感染和农药暴露之间的共同机制提供了见解,为帕金森病和涉及α-突触核蛋白修饰的相关病理提供了潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Infection and herbicide exposure implicate c-Abl kinase in α-Synuclein Ser129 phosphorylation.

Background: Parkinson's disease is a complex, multifactorial neurodegenerative disorder characterized by aggregation of α-Synuclein into Lewy bodies, with phosphorylation at serine 129 (pSer129), serving as a key regulatory site and pathological hallmark. However, the exact mechanisms by which environmental triggers lead to this disease phenotype remain poorly understood. In this study, we investigate the impact of representative infectious and pesticide exposures on pSer129 α-Synuclein, with a particular focus on the role of cellular kinases in mediating this process.

Methods: Neuronal cells were exposed to two distinct environmental stressors: the pesticide rotenone and the well-characterized gastric bacterium Helicobacter pylori (H. pylori). Phosphorylation of Ser129 α-Synuclein and mitochondrial damage were assessed by immunofluorescence staining or Western blotting. To investigate the involvement of c-Abl, cells were treated with mechanistically distinct c-Abl inhibitors and siRNA. Levels of pSer129 α-Synuclein were quantified by Western blotting, while the activities of the upstream serine/threonine kinase were predicted by kinase profiling and validated by Western blotting. Additionally, transcriptome analyses of treated cells were performed and ingenuity pathway analysis and DESeq2 were applied to identify neurodegenerative pathways affected by the infection/treatment.

Results: The functional analysis of our RNA-sequencing data revealed that both H. pylori and rotenone induce neuroinflammatory and cellular stress response pathways. Although they likely activate c-Abl through distinct upstream mediators, both triggers ultimately promote α-synuclein phosphorylation. Treatment with the c-Abl inhibitors, Ponatinib and Asciminib, effectively prevented the accumulation of pSer129 α-synuclein and reversed the associated gene expression changes induced by H. pylori or rotenone. Additionally, GSK3β has been identified as a contributor to Ser129 phosphorylation occurring downstream of activated c-Abl signaling. Notably, the vacuolating cytotoxin (VacA) produced by H. pylori appears to play a critical role in c-Abl-mediated phosphorylation of α-synuclein at Ser129.

Conclusions: These findings highlight the pivotal role of c-Abl in α-Synucleinopathies and provide insights into shared mechanisms between infection and pesticide exposure, offering potential therapeutic targets for Parkinson's disease and related pathologies involving α-Synuclein modification.

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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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