Human glia can both induce and rescue aspects of disease phenotype in Huntington disease.
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.
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Abdellatif
A
Benraiss
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Su
S
Wang
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Stephanie
S
Herrlinger
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Xiaojie
X
Li
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Devin
D
Chandler-Militello
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Joseph
J
Mauceri
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Hayley B
HB
Burm
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Michael
M
Toner
Center for Basic and Translational Neuroscience, University of Copenhagen, 2200 Copenhagen, Denmark.
Mikhail
M
Osipovitch
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Qiwu
Q
Jim Xu
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Fengfei
F
Ding
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Fushun
F
Wang
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Ning
N
Kang
Department of Anatomy and Cell Biology, New York Medical College, Valhalla, New York 10595, USA.
Jian
J
Kang
Psychogenics, Inc., Tarrytown, New York 10591, USA.
Paul C
PC
Curtin
Psychogenics, Inc., Tarrytown, New York 10591, USA.
Daniela
D
Brunner
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Martha S
MS
Windrem
CHDI Foundation and CHDI Management, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, USA.
Ignacio
I
Munoz-Sanjuan
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.|Center for Basic and Translational Neuroscience, University of Copenhagen, 2200 Copenhagen, Denmark.
Maiken
M
Nedergaard
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York 14642, USA.|Center for Basic and Translational Neuroscience, University of Copenhagen, 2200 Copenhagen, Denmark.|Neuroscience Center, Rigshospitalet, 2100 Copenhagen, Denmark.
Steven A
SA
Goldman
D000818:Animals; D001522:Behavior, Animal; D002678:Chimera / Q000378:metabolism; D003071:Cognition; D003433:Crosses, Genetic; D018450:Disease Progression; D005260:Female; D000066449:Human Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism; D006816:Huntington Disease / Q000473:pathology*; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity; D017072:Neostriatum / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D033581:Stem Cell Transplantation; D016019:Survival Analysis
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D018960:Hyaluronan Receptors