Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity.
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.
Shin
Ji-Yeon
JY
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Fang
Zhi-Hui
ZH
Yu
Zhao-Xue
ZX
Wang
Chuan-En
CE
Li
Shi-Hua
SH
Li
Xiao-Jiang
XJ
D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism* / Q000633:toxicity
D027342:Excitatory Amino Acid Transporter 2; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D018698:Glutamic Acid