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

Publication date: Feb 27, 2020

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.

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Wu, Z., Parry, M., Hou, X.Y., Liu, M.H., Wang, H., Cain, R., Pei, Z.F., Chen, Y.C., Guo, Z.Y., Abhijeet, S., and Chen, G. Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease. 06957. 2020 Nat Commun (11):1.

Concepts Keywords
Action Potentials External globus pallidus
Astrocyte Pars reticulata
Astrocytes NEUROD1
Axons Astrocyte
Ectopic Expression Globus pallidus
GABAergic Neurodegeneration
Globus Pallidus Striatum
Huntingtin Substantia nigra
Huntington Medium spiny neuron
Medium Spiny Neurons Basal ganglia
Mutation Brain
Neurodegenerative Disorders AtN conversion disease
Neuron
Neurons
Striatal
Striatum
Substantia Nigra
Synaptic
Transcription Factors

Semantics

Type Source Name
drug DRUGBANK L-Glutamine
disease MESH separated
disease MESH movement disorders
drug DRUGBANK Tetrabenazine
drug DRUGBANK Spinosad
disease MESH atrophy
drug DRUGBANK Coenzyme M
disease MESH neurodegenerative disorders

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