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

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 model...

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Bibliographic Details
Published in:Nature communications Vol. 11; no. 1; pp. 1105 - 18
Main Authors: Wu, Zheng, Parry, Matthew, Hou, Xiao-Yi, Liu, Min-Hui, Wang, Hui, Cain, Rachel, Pei, Zi-Fei, Chen, Yu-Chen, Guo, Zi-Yuan, Abhijeet, Sambangi, Chen, Gong
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 27.02.2020
Nature Publishing Group
Nature Portfolio
Subjects:
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
ISSN:2041-1723, 2041-1723
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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-14855-3