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Sci. STKE, 3 January 2006
Vol. 2006, Issue 316, p. tw462
[DOI: 10.1126/stke.3162006tw462]

EDITORS' CHOICE

NEURODEGENERATION A Role for Glia in Huntington's Disease?

Huntington's disease (HD), a devastating neurodegenerative disorder caused by an expanded polyglutamine tract in the protein huntingtin (htt), is characterized by the preferential loss of medium-sized spiny neurons (MSNs) in the striatum. Noting that htt is found in glia, as well as in neurons, and that MSNs receive abundant glutamatergic input (making them vulnerable to excitotoxicity), Shin et al. investigated the possible role of glial dysfunction in contributing to the pathophysiology of HD. The authors used immunogold labeling and immunofluorescence analysis to demonstrate the existence of intranuclear aggregates of htt in glia in the brains of R6/2 mice (a transgenic mouse model of HD). Intranuclear aggregates of htt were also found in glia of a second mouse model of HD and in brains of HD patients. The prevalence of nuclear htt aggregates in R6/2 glia increased with age and correlated temporally with a decrease in the abundance of glutamate transporter 1 (GLT-1). Consistent with the decrease in GLT-1, R6/2 brain slices showed decreased dihydrokainate-inhibitable glutamate uptake compared with wild-type brain slices, and this difference became more prominent with age. Coculture with wild-type astrocytes attenuated signs of neuronal degeneration in neurons overexpressing mutant htt, whereas coculture with glia expressing mutant htt promoted the degeneration of wild-type neurons. Moreover, wild-type astrocytes were better than R6/2 astrocytes at protecting neurons from glutamate-mediated toxicity. Thus, the authors suggest that expression of mutant htt in glia may lead to decreased glutamate uptake and thereby contribute to excitotoxic neuronal death.

J.-Y. Shin, Z.-H. Fang, Z.-X. Yu, C.-E. Wang, S.-H. Li, X.-J. Li, Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 171, 1001-1012 (2005). [Abstract] [Full Text]

Citation: A Role for Glia in Huntington's Disease? Sci. STKE 2006, tw462 (2006).



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