帕金森病 iPSC 衍生多巴胺神经元中细胞α-突触核蛋白病理学与生物能量功能障碍有关。

Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson's iPSC-derived dopamine neurons.

机构信息

The Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.

Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK.

出版信息

Hum Mol Genet. 2019 Jun 15;28(12):2001-2013. doi: 10.1093/hmg/ddz038.

DOI:10.1093/hmg/ddz038

PMID:30753527

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6548224/

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder and a central role for α-synuclein (αSyn; SNCA) in disease aetiology has been proposed based on genetics and neuropathology. To better understand the pathological mechanisms of αSyn, we generated induced pluripotent stem cells (iPSCs) from healthy individuals and PD patients carrying the A53T SNCA mutation or a triplication of the SNCA locus and differentiated them into dopaminergic neurons (DAns). iPSC-derived DAn from PD patients carrying either mutation showed increased intracellular αSyn accumulation, and DAns from patients carrying the SNCA triplication displayed oligomeric αSyn pathology and elevated αSyn extracellular release. Transcriptomic analysis of purified DAns revealed perturbations in expression of genes linked to mitochondrial function, consistent with observed reduction in mitochondrial respiration, impairment in mitochondrial membrane potential, aberrant mitochondrial morphology and decreased levels of phosphorylated DRP1Ser616. Parkinson's iPSC-derived DAns showed increased endoplasmic reticulum stress and impairments in cholesterol and lipid homeostasis. Together, these data show a correlation between αSyn cellular pathology and deficits in metabolic and cellular bioenergetics in the pathology of PD.

摘要

帕金森病（PD）是第二常见的神经退行性疾病，基于遗传学和神经病理学，α-突触核蛋白（αSyn；SNCA）在疾病发病机制中起核心作用。为了更好地了解 αSyn 的病理机制，我们从健康个体和携带 A53T SNCA 突变或 SNCA 基因座三倍体的 PD 患者中生成诱导多能干细胞（iPSC），并将其分化为多巴胺能神经元（DAns）。携带任何一种突变的 PD 患者来源的 iPSC 衍生的 DAn 显示细胞内 αSyn 积累增加，而携带 SNCA 三倍体的患者来源的 DAns 显示寡聚 αSyn 病理学和升高的 αSyn 细胞外释放。纯化的 DAns 的转录组分析显示与线粒体功能相关的基因表达受到干扰，与观察到的线粒体呼吸减少、线粒体膜电位损伤、异常的线粒体形态和磷酸化 DRP1Ser616 水平降低一致。帕金森病 iPSC 衍生的 DAns 显示内质网应激增加，胆固醇和脂质稳态受损。综上所述，这些数据表明在 PD 病理中，αSyn 的细胞病理学与代谢和细胞生物能量学缺陷之间存在相关性。