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Giehrl-Schwab, J. ; Giesert, F. ; Rauser, B. ; Lao, C.L. ; Hembach, S. ; Lefort, S. ; Ibarra Del Rio, I.A. ; Koupourtidou; C. ; Luecken, M. ; Truong, D.-J.J. ; Fischer-Sternjak, J. ; Masserdotti, G. ; Prakash, N.* ; Ninkovic, J. ; Hölter, S.M. ; Vogt Weisenhorn, D.M. ; Theis, F.J. ; Götz, M. ; Wurst, W.

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

EMBO Mol. Med.:e14797 (2022)

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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

Corresponding Author

Keywords Astrocytes ; Crispra ; Gabaergic Neurons ; Parkinson's Disease ; Reprogramming

ISSN (print) / ISBN 1757-4676

e-ISSN 1757-4684

Journal EMBO Molecular Medicine

Quellenangaben Article Number: e14797

Publisher Wiley

Publishing Place Chichester

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Developmental Genetics (IDG)
Institute of Stem Cell Research (ISF)
Institute of Diabetes and Obesity (IDO)
Institute of Computational Biology (ICB)
Institute of Experimental Genetics (IEG)

Grants Helmholtz Association
Else Kröner-Fresenius-Stiftung (EKFS)
Chan Zuckerberg Initiative (CZI)