Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons.
EMBO Mol Med. 2022 Apr 4:e14797. doi: 10.15252/emmm.202114797. Epub ahead of print. PMID: 35373464.
|Authors/Editors:||Giehrl-Schwab J, Giesert F, Rauser B, Lao CL, Hembach S, Lefort S, Ibarra IL, Koupourtidou C, Luecken MD, Truong DJ, Fischer-Sternjak J, Masserdotti G, Prakash N, Ninkovic J, Giehrl-Schwab J, Giesert F, Rauser B, Lao CL, Hembach S, Lefort S, Ibarra IL, Koupourtidou C, Luecken MD, Truong DJ, Fischer-Sternjak J, Masserdotti G, Prakash N, Ninkovic J, Hölter SM, Vogt Weisenhorn DM, Theis FJ, Götz M, Wurst W.|
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.