Alpha-synuclein SNCA has been implicated in the etiology of Parkinson’s disease (PD); however, the normal function of alpha-synuclein protein and the pathway that mediates its pathogenic effect is yet to be discovered. We investigated the mechanistic role of SNCA in the nucleus utilizing isogenic human-induced pluripotent stem cells-derived neurons from PD patients with autosomal dominant mutations, A53T and SNCA-triplication, and their corresponding corrected lines by genome- and epigenome-editing. Comparisons of shape and integrity of the nuclear envelope and its resistance to stresses found that both mutations result in similar nuclear envelope perturbations that were reversed in the isogenic mutation-corrected cells. Further mechanistic studies showed that SNCA mutation has adverse effects on the nucleus by trapping Ras-related nuclear protein (RAN) and preventing it from transporting key nuclear proteins such as, DNMT3A, for maintaining normal nuclear function. For the first time, we proposed that α-syn interacts with RAN and normally functions in the nucleocytoplasmic transport while exerts its pathogenic effect by sequestering RAN. We suggest that defects in the nucleocytoplasmic transport components may be a general pathomechanistic driver of neurodegenerative diseases.

中文翻译：

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α-突触核蛋白在细胞核中的机制作用：家族性帕金森病 SNCA 突变引起的核功能受损。

α-突触核蛋白SNCA与帕金森病 (PD) 的病因有关；然而，α-突触核蛋白的正常功能和介导其致病作用的途径尚未被发现。我们利用来自具有常染色体显性突变、A53T 和 SNCA 三倍体的 PD 患者的等基因人类诱导多能干细胞衍生的神经元，以及通过基因组和表观基因组编辑相应的校正系，研究了SNCA在细胞核中的机制作用。对核膜的形状和完整性及其抗应激能力的比较发现，两种突变都会导致类似的核膜扰动，而这些扰动在同基因突变校正的细胞中却被逆转。进一步的机制研究表明，SNCA突变通过捕获 Ras 相关核蛋白 (RAN) 并阻止其转运关键核蛋白（如 DNMT3A）来维持正常的核功能，从而对细胞核产生不利影响。我们首次提出α-syn与RAN相互作用，通常在核质运输中发挥作用，同时通过隔离RAN发挥其致病作用。我们认为核细胞质运输成分的缺陷可能是神经退行性疾病的一般病理机制驱动因素。