Open AccessParkinson's disease motor symptoms rescue by CRISPRa‐reprogramming astrocytes into GABAergic neurons
Author(s) -
GiehrlSchwab Jessica,
Giesert Florian,
Rauser Benedict,
Lao Chu Lan,
Hembach Sina,
Lefort Sandrine,
Ibarra Ignacio L,
Koupourtidou Christina,
Luecken Malte Daniel,
Truong DongJiunn Jeffery,
FischerSternjak Judith,
Masserdotti Giacomo,
Prakash Nilima,
Ninkovic Jovica,
Hölter Sabine M,
Vogt Weisenhorn Daniela M,
Theis Fabian J,
Götz Magdalena,
Wurst Wolfgang
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114797
Subject(s) - library science , conceptualization , sociology , computer science , artificial intelligence
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.