Polyglutamine-expanded Huntingtin Promotes Sensitization of N-Methyl-D-aspartate Receptors via Post-synaptic Density 95

Ying Sun, Anneli Savanenin, P. Hemachandra Reddy, Ya Fang Liu

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)24713-24718
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number27
DOIs
StatePublished - Jul 6 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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