CRISPR-Cas9 Gene Editing Protects from the A53T-SNCA Overexpression-Induced Pathology of Parkinson's Disease in Vivo

Hyung Ho Yoon, Sunghyeok Ye, Sunhwa Lim, Ara Jo, Hawon Lee, Felix Hong, Seung Eun Lee, Soo Jin Oh, Na Rae Kim, Kyoungmi Kim, Bum Joon Kim, Hyunjin Kim, C. Justin Lee, Min Ho Nam, Junseok W. Hur, Sang Ryong Jeon

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in specific genes, including synuclein alpha (SNCA) 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 SNCA (A53T-SNCA) is a well-studied familial pathologic mutation in PD. However, techniques for deletion of the mutated SNCA gene in vivo have not been developed. Here, we used the CRISPR-Cas9 system to delete A53T-SNCA in vitro as well as in vivo. Adeno-associated virus carrying SaCas9-KKH with a single-guide RNA targeting A53T-SNCA significantly reduced A53T-SNCA expression levels in vitro. Furthermore, we tested its therapeutic potential in vivo 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.

Original languageEnglish
Pages (from-to)95-108
Number of pages14
JournalCRISPR Journal
Volume5
Issue number1
DOIs
Publication statusPublished - 2022 Feb
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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