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

EMBO Mol Med. 2022 May 9;14(5):e14797. doi: 10.15252/emmm.202114797. Epub 2022 Apr 4.


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.

Keywords: CRISPRa; GABAergic neurons; Parkinson's disease; astrocytes; reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes
  • Corpus Striatum
  • Dopamine
  • Dopaminergic Neurons
  • GABAergic Neurons
  • Mice
  • Parkinson Disease* / genetics
  • Parkinson Disease* / therapy


  • Dopamine

Associated data

  • GEO/GSE149872