Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA, 50011, USA.
Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, 50011, USA.
J Neuroimmune Pharmacol. 2019 Dec;14(4):595-607. doi: 10.1007/s11481-019-09844-3. Epub 2019 Mar 16.
Chronic and debilitating neurodegenerative diseases, such as Parkinson's disease (PD), impose an immense medical, emotional, and economic burden on patients and society. Due to a complex interaction between genetic and environmental risk factors, the etiology of PD remains elusive. However, the cumulative evidence emerging from clinical and experimental research over the last several decades has identified mitochondrial dysfunction, oxidative stress, neuroinflammation, and dysregulated protein degradation as the main drivers of PD neurodegeneration. The genome-editing system CRISPR (clustered regularly interspaced short palindromic repeats) has recently transformed the field of biotechnology and biomedical discovery and is poised to accelerate neurodegenerative disease research. It has been leveraged to generate PD animal models, such as Parkin, DJ-1, and PINK1 triple knockout miniature pigs. CRISPR has also allowed the deeper understanding of various PD gene interactions, as well as the identification of novel apoptotic pathways associated with neurodegenerative processes in PD. Furthermore, its application has been used to dissect neuroinflammatory pathways involved in PD pathogenesis, such as the PKCδ signaling pathway, as well as the roles of novel compensatory or protective pathways, such as Prokineticin-2 signaling. This review aims to highlight the historical milestones in the evolution of this technology and attempts to illustrate its transformative potential in unraveling disease mechanisms as well as in the development of innovative treatment strategies for PD. Graphical Abstract.
慢性和进行性神经退行性疾病，如帕金森病 (PD)，给患者和社会带来了巨大的医疗、情感和经济负担。由于遗传和环境风险因素之间的复杂相互作用，PD 的病因仍然难以捉摸。然而，过去几十年的临床和实验研究的综合证据已经确定了线粒体功能障碍、氧化应激、神经炎症和失调的蛋白质降解是 PD 神经退行性变的主要驱动因素。基因组编辑系统 CRISPR（成簇的、规律间隔的短回文重复序列）最近改变了生物技术和生物医学发现领域，有望加速神经退行性疾病的研究。它已被用于生成 PD 动物模型，如 Parkin、DJ-1 和 PINK1 三重敲除小型猪。CRISPR 还允许更深入地了解各种 PD 基因相互作用，并确定与 PD 神经退行性过程相关的新凋亡途径。此外，它的应用还用于剖析与 PD 发病机制相关的神经炎症途径，如 PKCδ 信号通路，以及新的代偿或保护途径的作用，如 Prokineticin-2 信号通路。这篇综述旨在强调该技术发展的历史里程碑，并尝试说明其在揭示疾病机制以及开发 PD 创新治疗策略方面的变革潜力。
