Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Kyung Hee University, Seoul, Korea.
RnD center, GeneCker, Seoul, Korea; Kyung Hee University, Seoul, Korea.
CRISPR J. 2022 Feb;5(1):95-108. doi: 10.1089/crispr.2021.0025.
Mutations in specific genes, including synuclein alpha () that encodes the α-synuclein protein, are known to be risk factors for sporadic Parkinson's disease (PD), as well as critical factors for familial PD. In particular, A53T-mutated (A53T-SNCA) is a well-studied familial pathologic mutation in PD. However, techniques for deletion of the mutated gene have not been developed. Here, we used the CRISPR-Cas9 system to delete A53T-SNCA as well as . Adeno-associated virus carrying SaCas9-KKH with a single-guide RNA targeting A53T-SNCA significantly reduced A53T-SNCA expression levels . Furthermore, we tested its therapeutic potential in a viral A53T-SNCA-overexpressing rat model of PD. Gene deletion of A53T-SNCA significantly rescued the overexpression of α-synuclein, reactive microgliosis, dopaminergic neurodegeneration, and parkinsonian motor symptoms. Our findings propose CRISPR-Cas9 system as a potential prevention strategy for A53T-SNCA-specific PD.
特定基因的突变，包括编码α-突触核蛋白的突触核蛋白α（synuclein alpha ()），已知是散发性帕金森病（PD）的风险因素，也是家族性 PD 的关键因素。特别是，A53T 突变的 （A53T-SNCA）是 PD 中研究充分的家族性病理突变。然而，尚未开发出删除突变 基因的技术。在这里，我们使用 CRISPR-Cas9 系统删除 A53T-SNCA 以及 。携带靶向 A53T-SNCA 的单引导 RNA 的 SaCas9-KKH 的腺相关病毒显著降低了 A53T-SNCA 的表达水平。此外，我们在 PD 的病毒 A53T-SNCA 过表达大鼠模型中测试了其治疗潜力。A53T-SNCA 的基因缺失显著挽救了α-突触核蛋白的过表达、反应性小胶质细胞增生、多巴胺能神经退行性变和帕金森病运动症状。我们的研究结果提出 CRISPR-Cas9 系统作为针对 A53T-SNCA 特异性 PD 的潜在预防策略。
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