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

EMBO Mol. Med.:e14797 (2022)
Publ. Version/Full Text Research data DOI
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Astrocytes ; Crispra ; Gabaergic Neurons ; Parkinson's Disease ; Reprogramming
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Quellenangaben Volume: , Issue: , Pages: , Article Number: e14797 Supplement: ,
Publisher Wiley
Publishing Place Chichester
Reviewing status Peer reviewed
Grants Helmholtz Association
Else Kröner-Fresenius-Stiftung (EKFS)
Chan Zuckerberg Initiative (CZI)