Highlights d Proteomics define the NSC niche-specific extracellular matrix d Detergent-solubility profiling reveals extracellular matrix architecture d Transglutaminase 2 regulates neurogenesis d Stiffness is increased in the neurogenic niches of the brain

No 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.