TY - JOUR
T1 - Polyglutamine-expanded Huntingtin Promotes Sensitization of N-Methyl-D-aspartate Receptors via Post-synaptic Density 95
AU - Sun, Ying
AU - Savanenin, Anneli
AU - Reddy, P. Hemachandra
AU - Liu, Ya Fang
PY - 2001/7/6
Y1 - 2001/7/6
N2 - Increased glutamate-mediated excitotoxicity seems to play an important role in the pathogenesis of Huntington's disease (Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taaman, J. W., Cooper, J. M., and Schapira, A. H. (1999) Ann. Neurol. 45, 25-32). However, how polyglutamine expansion in huntingtin promotes glutamate-mediated excitotoxicity remains a mystery. In this study we provide evidence that (i) normal huntingtin is associated with N-methyl-D-aspartate (NMDA) and kainate receptors via postsynaptic density 95 (PSD-95), (ii) the SH3 domain of PSD-95 mediates its binding to huntingtin, and (iii) polyglutamine expansion interferes with the ability of huntingtin to interact with PSD-95. The expression of polyglutamine-expanded huntingtin causes sensitization of NMDA receptors and promotes neuronal apoptosis induced by glutamate. The addition of the NMDA receptor antagonist significantly attenuates neuronal toxicity induced by glutamate and polyglutamine-expanded huntingtin. The overexpression of normal huntingtin significantly inhibits neuronal toxicity mediated by NMDA or kainate receptors. Our results demonstrate that polyglutamine expansion impairs the ability of huntingtin to bind PSD-95 and inhibits glutamate-mediated excitotoxicity. These changes may be essential for the pathogenesis of Huntington's disease.
AB - Increased glutamate-mediated excitotoxicity seems to play an important role in the pathogenesis of Huntington's disease (Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taaman, J. W., Cooper, J. M., and Schapira, A. H. (1999) Ann. Neurol. 45, 25-32). However, how polyglutamine expansion in huntingtin promotes glutamate-mediated excitotoxicity remains a mystery. In this study we provide evidence that (i) normal huntingtin is associated with N-methyl-D-aspartate (NMDA) and kainate receptors via postsynaptic density 95 (PSD-95), (ii) the SH3 domain of PSD-95 mediates its binding to huntingtin, and (iii) polyglutamine expansion interferes with the ability of huntingtin to interact with PSD-95. The expression of polyglutamine-expanded huntingtin causes sensitization of NMDA receptors and promotes neuronal apoptosis induced by glutamate. The addition of the NMDA receptor antagonist significantly attenuates neuronal toxicity induced by glutamate and polyglutamine-expanded huntingtin. The overexpression of normal huntingtin significantly inhibits neuronal toxicity mediated by NMDA or kainate receptors. Our results demonstrate that polyglutamine expansion impairs the ability of huntingtin to bind PSD-95 and inhibits glutamate-mediated excitotoxicity. These changes may be essential for the pathogenesis of Huntington's disease.
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U2 - 10.1074/jbc.M103501200
DO - 10.1074/jbc.M103501200
M3 - Article
C2 - 11319238
AN - SCOPUS:0035816627
SN - 0021-9258
VL - 276
SP - 24713
EP - 24718
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 27
ER -