Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95.
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.
Sun
Y
Y
Department of Pharmaceutical Sciences, Northeastern University, 715 Albany St., Boston, MA 02115, USA.
Savanenin
A
A
Reddy
P H
PH
Liu
Y F
YF
D000818:Animals; D002460:Cell Line; D000076122:Disks Large Homolog 4 Protein; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008970:Molecular Weight; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D018092:Kainic Acid Receptors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014162:Transfection; D018909:src Homology Domains
D000076122:Disks Large Homolog 4 Protein; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C501449:Dlg4 protein, rat; C086055:HTT protein, human; C499524:Htt protein, rat; C033652:postsynaptic density proteins; C097188:polyglutamine