MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh EH9 3JQ, UK.
Nat Commun. 2011 Aug 23;2:440. doi: 10.1038/ncomms1453.
A major barrier to research on Parkinson's disease is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells from patients and differentiate them into neurons affected by disease. Triplication of SNCA, encoding α-synuclein, causes a fully penetrant, aggressive form of Parkinson's disease with dementia. α-Synuclein dysfunction is the critical pathogenic event in Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. Here we produce multiple induced pluripotent stem cell lines from an SNCA triplication patient and an unaffected first-degree relative. When these cells are differentiated into midbrain dopaminergic neurons, those from the patient produce double the amount of α-synuclein protein as neurons from the unaffected relative, precisely recapitulating the cause of Parkinson's disease in these individuals. This model represents a new experimental system to identify compounds that reduce levels of α-synuclein, and to investigate the mechanistic basis of neurodegeneration caused by α-synuclein dysfunction.
帕金森病研究的一个主要障碍是无法获得用于研究的病变组织。一种解决方案是从患者中提取诱导多能干细胞，并将其分化为受疾病影响的神经元。编码α-突触核蛋白的 SNCA 三倍体导致具有痴呆的完全穿透性、侵袭性帕金森病形式。α-突触核蛋白功能障碍是帕金森病、多系统萎缩和路易体痴呆的关键致病事件。在这里，我们从 SNCA 三倍体患者和未受影响的一级亲属中产生了多个诱导多能干细胞系。当这些细胞分化为中脑多巴胺能神经元时，来自患者的神经元产生的α-突触核蛋白是未受影响的相对神经元的两倍，这正是这些个体中帕金森病的病因。该模型代表了一种新的实验系统，可以鉴定降低α-突触核蛋白水平的化合物，并研究由α-突触核蛋白功能障碍引起的神经退行性变的机制基础。
