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α-突触核蛋白与微管组织相互作用与帕金森病患者来源的神经元细胞突起完整性受损有关。

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson's Patient-Derived Neuronal Cells.

机构信息

Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander Universität, Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.

Systematic Proteome Research & Bioanalytics, Institute for Experimental Medicine, Christian-Albrechts-Universität zu Kiel, 24105 Kiel, Germany.

出版信息

Int J Mol Sci. 2022 Feb 5;23(3):1812. doi: 10.3390/ijms23031812.

DOI:10.3390/ijms23031812
PMID:35163733
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8836605/
Abstract

Parkinson's disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by several studies using cell-free model systems. In this study, we investigate the impact of aSyn on microtubule organization in aSyn overexpressing H4 neuroglioma cells and midbrain dopaminergic neuronal cells (mDANs) generated from PD patient-derived human induced pluripotent stem cells (hiPSCs) carrying an aSyn gene duplication (). An unbiased mass spectrometric analysis reveals a preferential binding of aggregated aSyn conformers to a number of microtubule elements. We confirm the interaction of aSyn with beta tubulin III in H4 and hiPSC-derived mDAN cell model systems, and demonstrate a remarkable redistribution of tubulin isoforms from the soluble to insoluble fraction, accompanied by a significantly increased insoluble aSyn level. Concordantly, mDANs show impaired neuritic phenotypes characterized by perturbations in neurite initiation and outgrowth. In summary, our findings suggest a mechanistic pathway, through which aSyn aggregation interferes with microtubule organization and induces neurite impairments.

摘要

帕金森病（PD）的神经病理学特征是多巴胺能神经元丧失和聚集的α-突触核蛋白（aSyn）沉积。越来越多的证据表明，在 PD 中，神经突变性先于神经元丧失。一种可能的潜在机制可能是 aSyn 干扰神经突发育中的微管组织，这是几项使用无细胞模型系统的研究所暗示的。在这项研究中，我们研究了 aSyn 对过表达 aSyn 的 H4 神经胶质瘤细胞和从中枢多巴胺能神经元（mDAN）中产生的微管组织的影响，这些 mDAN 是由携带 aSyn 基因重复（）的 PD 患者来源的人诱导多能干细胞（hiPSC）产生的。一项无偏见的质谱分析揭示了聚集的 aSyn 构象优先与许多微管元件结合。我们在 H4 和 hiPSC 衍生的 mDAN 细胞模型系统中证实了 aSyn 与β-微管蛋白 III 的相互作用，并证明了微管蛋白同工型从可溶性部分到不溶性部分的显著重分布，同时不溶性 aSyn 水平显著增加。一致地，mDAN 显示出神经突表型受损的特征，表现为神经突起始和生长的干扰。总之，我们的发现表明了一种机制途径，通过该途径，aSyn 聚集干扰微管组织并诱导神经突损伤。

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