Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons
Giehrl-Schwab J, Giesert F, Rauser B, Lao CL, Hembach S, Lefort S, Ibarra IL, Koupourtidou C, Luecken MD, Truong DJJ, Fischer-Sternjak J, Masserdotti G, Prakash N, Ninkovic J, Hoelter SM, Weisenhorn DMV, Theis FJ, Goetz M, Wurst W (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 14
Article Number: e14797
Journal Issue: 5
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.
Involved external institutions
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Hochschule Hamm-Lippstadt
Germany (DE)
Germany (DE)
Hochschule Hamm-Lippstadt
Germany (DE)
How to cite
APA:
Giehrl-Schwab, J., Giesert, F., Rauser, B., Lao, C.L., Hembach, S., Lefort, S.,... Wurst, W. (2022). Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons. Embo Molecular Medicine, 14(5). https://doi.org/10.15252/emmm.202114797
MLA:
Giehrl-Schwab, Jessica, et al. "Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons." Embo Molecular Medicine 14.5 (2022).
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