Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons

Giehrl-Schwab, Jessica; Giesert, Florian; Rauser, Benedict; Lao, Chu Lan; Hembach, Sina; Lefort, Sandrine; Ibarra, Ignacio L.; Koupourtidou, Christina; Luecken, Malte Daniel; Truong, Dong-Jiunn Jeffery; Fischer-Sternjak, Judith; Masserdotti, Giacomo; Prakash, Nilima; Ninkovic, Jovica; Hoelter, Sabine M.; Weisenhorn, Daniela M. Vogt; Theis, Fabian J.; Goetz, Magdalena and Wurst, Wolfgang (2022): Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons. In: EMBO Molecular Medicine, Vol. 14, No. 5, e14797

Abstract

Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock-in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV-based strategy carrying intein-split-dCas9 in combination with activators (AAV-dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single-cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6-OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV-dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease.

• Item Type: Journal article
• Faculties: Medicine; Medicine > Munich Cluster for Systems Neurology (SyNergy)
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1757-4676
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198