Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

Abdellatif Benraiss, Su Wang, Stephanie Herrlinger, Xiaojie Li, Devin Chandler-Militello, Joseph Mauceri, Hayley B. Burm, Michael Toner, Mikhail Osipovitch, Qiwu Jim Xu, Fengfei Ding, Fushun Wang, Ning Kang, Jian Kang, Paul C. Curtin, Daniela Brunner, Martha S. Windrem, Ignacio Munoz-Sanjuan, Maiken Nedergaard and Steven A. Goldman ()
Additional contact information
Abdellatif Benraiss: Center for Translational Neuromedicine, University of Rochester Medical Center
Su Wang: Center for Translational Neuromedicine, University of Rochester Medical Center
Stephanie Herrlinger: Center for Translational Neuromedicine, University of Rochester Medical Center
Xiaojie Li: Center for Translational Neuromedicine, University of Rochester Medical Center
Devin Chandler-Militello: Center for Translational Neuromedicine, University of Rochester Medical Center
Joseph Mauceri: Center for Translational Neuromedicine, University of Rochester Medical Center
Hayley B. Burm: Center for Translational Neuromedicine, University of Rochester Medical Center
Michael Toner: Center for Translational Neuromedicine, University of Rochester Medical Center
Mikhail Osipovitch: Center for Basic and Translational Neuroscience, University of Copenhagen
Qiwu Jim Xu: Center for Translational Neuromedicine, University of Rochester Medical Center
Fengfei Ding: Center for Translational Neuromedicine, University of Rochester Medical Center
Fushun Wang: Center for Translational Neuromedicine, University of Rochester Medical Center
Ning Kang: Center for Translational Neuromedicine, University of Rochester Medical Center
Jian Kang: New York Medical College
Paul C. Curtin: Psychogenics, Inc.
Daniela Brunner: Psychogenics, Inc.
Martha S. Windrem: Center for Translational Neuromedicine, University of Rochester Medical Center
Ignacio Munoz-Sanjuan: CHDI Foundation and CHDI Management, Inc.
Maiken Nedergaard: Center for Translational Neuromedicine, University of Rochester Medical Center
Steven A. Goldman: Center for Translational Neuromedicine, University of Rochester Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder.

Date: 2016
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DOI: 10.1038/ncomms11758

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