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

Author

Listed:
  • Zheng Wu

    (Pennsylvania State University)

  • Matthew Parry

    (Pennsylvania State University)

  • Xiao-Yi Hou

    (Pennsylvania State University)

  • Min-Hui Liu

    (Jinan University)

  • Hui Wang

    (Pennsylvania State University
    Southeast University)

  • Rachel Cain

    (Pennsylvania State University)

  • Zi-Fei Pei

    (Pennsylvania State University)

  • Yu-Chen Chen

    (Pennsylvania State University)

  • Zi-Yuan Guo

    (Pennsylvania State University)

  • Sambangi Abhijeet

    (Pennsylvania State University)

  • Gong Chen

    (Pennsylvania State University
    Jinan University)

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.

Suggested Citation

  • Zheng Wu & Matthew Parry & Xiao-Yi Hou & Min-Hui Liu & Hui Wang & Rachel Cain & Zi-Fei Pei & Yu-Chen Chen & Zi-Yuan Guo & Sambangi Abhijeet & Gong Chen, 2020. "Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14855-3
    DOI: 10.1038/s41467-020-14855-3
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    Cited by:

    1. Irene Molina-Gonzalez & Rebecca K. Holloway & Zoeb Jiwaji & Owen Dando & Sarah A. Kent & Katie Emelianova & Amy F. Lloyd & Lindsey H. Forbes & Ayisha Mahmood & Thomas Skripuletz & Viktoria Gudi & Jame, 2023. "Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Zengpeng Han & Nengsong Luo & Wenyu Ma & Xiaodong Liu & Yuxiang Cai & Jiaxin Kou & Jie Wang & Lei Li & Siqi Peng & Zihong Xu & Wen Zhang & Yuxiang Qiu & Yang Wu & Chaohui Ye & Kunzhang Lin & Fuqiang X, 2023. "AAV11 enables efficient retrograde targeting of projection neurons and enhances astrocyte-directed transduction," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Giorgia Maria Ferlazzo & Anna Maria Gambetta & Sonia Amato & Noemi Cannizzaro & Silvia Angiolillo & Mattia Arboit & Linda Diamante & Elena Carbognin & Patrizia Romani & Federico La Torre & Elena Galim, 2023. "Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

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