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

Abstract

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

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Acknowledgments

The writing of this review was primarily supported by the National Institutes of Health R01 grants ES027245, ES026892, NS100090 and NS088206. AAW and QW were supported by the College of Human Sciences at Iowa State University, National Institutes of Health R00 grant AG047282, and Alzheimer’s Association Research Grant to Promote Diversity (AARG-D) AARGD-17-529552. The W. Eugene and Linda Lloyd Endowed Chair and Eminent scholar and Armbrust Endowment to A.G.K. and the Salisbury chair to A.K. are also acknowledged. The support from the Presidential Interdisciplinary Research Initiative for the Big Data Brain Research from Iowa State University is also acknowledged.

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Correspondence to Anumantha G. Kanthasamy.

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A.G.K and V.A have an equity interest in PK Biosciences Corporation located in Ames, IA. The terms of this arrangement have been reviewed and approved by Iowa State University in accordance with its conflict of interest policies. Other authors declare no actual or potential competing financial interests.

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Luo, J., Padhi, P., Jin, H. et al. Utilization of the CRISPR-Cas9 Gene Editing System to Dissect Neuroinflammatory and Neuropharmacological Mechanisms in Parkinson’s Disease. J Neuroimmune Pharmacol 14, 595–607 (2019). https://doi.org/10.1007/s11481-019-09844-3

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Keywords

  • CRISPR
  • Parkinson’s disease
  • Neurodegeneration
  • Neuroinflammation
  • Drug development
  • PKCdelta