Utilization of the CRISPR-Cas9 Gene Editing System to Dissect Neuroinflammatory and Neuropharmacological Mechanisms in Parkinson's Disease.

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.