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J. Cell Biol. 171 (6): 1001-1012

Copyright © 2005 by the Rockefeller University Press.


Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity

Ji-Yeon Shin, Zhi-Hui Fang, Zhao-Xue Yu, Chuan-En Wang, Shi-Hua Li, , and Xiao-Jiang Li

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322

Correspondence to Xiao-Jiang Li: xiaoli{at}

Abstract: Huntington disease (HD) is characterized by the preferential loss of striatal medium-sized spiny neurons (MSNs) in the brain. Because MSNs receive abundant glutamatergic input, their vulnerability to excitotoxicity may be largely influenced by the capacity of glial cells to remove extracellular glutamate. However, little is known about the role of glia in HD neuropathology. Here, we report that mutant huntingtin accumulates in glial nuclei in HD brains and decreases the expression of glutamate transporters. As a result, mutant huntingtin (htt) reduces glutamate uptake in cultured astrocytes and HD mouse brains. In a neuron–glia coculture system, wild-type glial cells protected neurons against mutant htt-mediated neurotoxicity, whereas glial cells expressing mutant htt increased neuronal vulnerability. Mutant htt in cultured astrocytes decreased their protection of neurons against glutamate excitotoxicity. These findings suggest that decreased glutamate uptake caused by glial mutant htt may critically contribute to neuronal excitotoxicity in HD.

Abbreviations used in this paper: AD, Alzheimer's disease; DHK, dihydrokainate; DIV, days in vitro; GFAP, glial fibrillary acidic protein; GLT-1, glutamate transporter-1; GLAST, glutamate/aspartate transporter; HD, Huntington's disease; htt, huntingtin; MAP2, microtubule-associated protein 2; MSNs, medium-sized spiny neurons; MTT, 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PolyQ, polyglutamine.

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