Journal Article

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

Chen, Gong, Liu, Min-Hui, Wu, Zheng, Wang, Hui, Hou, Xiao-Yi, Cain, Rachel, Pei, Zi-Fei, Abhijeet, Sambangi, Chen, Yu-Chen, Parry, Matthew, Guo, Zi-Yuan

2020

Overview

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. In vivo reprogramming of reactive glia using transfection of a single transcription factor has been described before by these authors and applied to models of neurodegeneration. Here the authors use this procedure in the R6/2 mouse model of Huntington’s disease, targeting astrocytes in the striatum, converting them to GABAergic neurons.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 42 / 42/44 / 631/378/1689/1558 / 631/378/87 / Action Potentials - physiology / Animal models / Animals / Astrocytes / Astrocytes - physiology / Axon guidance / Axons / Basic Helix-Loop-Helix Transcription Factors / Behavior Observation Techniques / Behavior, Animal / Beta2 protein / Cellular Reprogramming Techniques - methods / Conversion / Corpus Striatum - cytology / Corpus Striatum - pathology / Dependovirus - genetics / Disease Models, Animal / Ectopic expression / Ectopic Gene Expression / GABAergic Neurons - physiology / Gene therapy / Genetic Therapy - methods / Genetic Vectors - administration & dosage / Genetic Vectors - genetics / Globus pallidus / HEK293 Cells / Homeodomain Proteins / Humanities and Social Sciences / Humans / Huntingtin / Huntingtin Protein - genetics / Huntington Disease - genetics / Huntington Disease - pathology / Huntington Disease - therapy / Huntington's disease / Huntingtons disease / In vivo methods and tests / Life span / Longevity / Mice / Mice, Transgenic / multidisciplinary / Mutation / Neostriatum / Neurodegeneration / Neurodegenerative diseases / Neuronal-glial interactions / Neurons / Patch-Clamp Techniques / Point mutation / Science / Science (multidisciplinary) / Spiny neurons / Stereotaxic Techniques / Substantia nigra / Time dependence / Transcription Factors / Transfection / γ-Aminobutyric acid