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

EMBO Molecular Medicine

Sandrine Lefort¹  Fabian J Theis²  Ignacio L Ibarra²  Malte Daniel Luecken²  Wolfgang Wurst³  Benedict Rauser³  Dong‐Jiunn Jeffery Truong³  Sina Hembach³  Sabine M Hölter³  Florian Giesert³  Daniela M Vogt Weisenhorn³  Jessica Giehrl‐Schwab³  Giacomo Masserdotti⁴  Jovica Ninkovic⁴  Christina Koupourtidou⁴  Chu Lan Lao⁴  Judith Fischer‐Sternjak⁴  Nilima Prakash⁵  Magdalena Götz⁶ 

[1] Institute for Diabetes and Obesity Helmholtz Center Munich Neuherberg Germany;Institute of Computational Biology Helmholtz Center Munich Neuherberg Germany;Institute of Developmental Genetics Helmholtz Center Munich Neuherberg Germany;Institute of Stem Cell Research Helmholtz Center Munich Neuherberg Germany;Laboratory of Applied Genetics and Stem Cell Biology Department Hamm 2 Hamm‐Lippstadt University of Applied Sciences Hamm Germany;Munich Cluster for Systems Neurology (SyNergy) Munich Germany;

关键词: astrocytes;    CRISPRa;    GABAergic neurons;    Parkinson's disease;    reprogramming;   

DOI  :  10.15252/emmm.202114797

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown