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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Astrocytes ; Crispra ; Gabaergic Neurons ; Parkinson's Disease ; Reprogramming
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Zeitschrift EMBO Molecular Medicine
Quellenangaben Band: , Heft: , Seiten: , Artikelnummer: e14797 Supplement: ,
Verlag Wiley
Verlagsort Chichester
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) 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)
Förderungen Helmholtz Association
Else Kröner-Fresenius-Stiftung (EKFS)
Chan Zuckerberg Initiative (CZI)