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Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease.


ABSTRACT: Huntington's disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32+ medium spiny neurons. The striatal astrocyte-converted neurons showed action potentials and synaptic events, and projected their axons to the targeted globus pallidus and substantia nigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treated R6/2 mice showed a significant extension of life span and improvement of motor functions. This study demonstrates that in vivo AtN conversion may be a disease-modifying gene therapy to treat HD and other neurodegenerative disorders.

SUBMITTER: Wu Z 

PROVIDER: S-EPMC7046613 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease.

Wu Zheng Z   Parry Matthew M   Hou Xiao-Yi XY   Liu Min-Hui MH   Wang Hui H   Cain Rachel R   Pei Zi-Fei ZF   Chen Yu-Chen YC   Guo Zi-Yuan ZY   Abhijeet Sambangi S   Chen Gong G  

Nature communications 20200227 1


Huntington's disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted n  ...[more]

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