Huntington's disease (HD) 1 is a dominant inherited neurodegenerative disorder characterized by choreiform movement, psychiatric disturbance, and cognitive decline (2). The HD gene encodes a 350-kDa protein designated as huntingtin (3), which is richly expressed in dendrites and nerve terminals, where huntingtin is associated with synaptic vesicles and microtubule complexes (4 -5). The defect of the HD gene is the expansion of a CAG repeat encoding polyglutamine at its 5Ј end, and the length of the repeat is correlated with the age of onset and the severity of the disease (6).Although the HD gene has been identified for many years, how polyglutamine-expanded huntingtin causes neurons to die remains unclear. Increased glutamate-mediated excitotoxicity in HD has been a very popular hypothesis for the last 25 years (1). The hypothesis is generated from findings that the intrastriatal injection of glutamate or kainic acid in rat causes selective loss of medium spiny neurons that are also selectively affected in HD (7-8). This hypothesis is supported further by the findings that NMDA receptors are hyperactive, and excitotoxicity mediated by these receptors is enhanced significantly in HD transgenic mice (9 -10). These results suggest that overactivation of glutamate receptors may play a significant role in the pathogenesis of HD. However, over 95% of normal or polyglutamine-expanded huntingtin is located in the cytoplasm (6 -7), whereas glutamate receptors are cell surface receptors. How a cytoplasmic protein alters glutamate receptors on the cell surface membrane is an intriguing question.PSD-95 is a scaffold protein that contains an SH3 domain, a GK domain, and three PDZ domains that bind to the NMDA receptor NR2 subunits and kainate receptor GluR6 subunit (11)(12). The binding of PSD-95 to NMDA or kainate receptors causes the clustering of the receptors in the postsynaptic membrane and regulates NMDA-dependent long term potentiation and long term depression (12). PSD-95 also binds to cytoplasmic signaling proteins and links the receptors to cellular signaling cascades (13)(14). In transgenic mice lacking PSD-95, the frequency function of NMDA-dependent long term potentiation and long term depression is shifted, and spatial learning is impaired severely (15). Suppression of PSD-95 expression inhibits NMDA receptor-mediated activation of nitric-oxide synthase and excitotoxicity (16). These studies suggest that PSD-95 regulates glutamate receptor-mediated excitotoxicity and plays an important role in spatial learning, which is severely impaired in HD patients and HD transgenic mice (17)(18)(19). In previous studies, we observed that the overexpression of polyglutamine-expanded huntingtin caused neuronal apoptosis via activation of the mixed lineage kinase/c-Jun N-terminal kinase signaling pathway (20 -21), and mixed lineage kinase is also involved in neuronal toxicity mediated by GluR6 receptors via interaction with . The present study is intended to investigate the "missing link" protein between glutamate receptor...