Huntington's disease (HD) is a progressive neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) tract in the huntingtin (htt) protein, resulting in selective neuronal loss in the striatum and cortex. Accumulating evidence suggests an involvement of NMDA receptor (NMDAR) overactivation in this process. Since NMDAR localization and function are dependent in part on interactions with cytoplasmic proteins and the actin cytoskeleton, and because various binding partners of htt are involved in regulation of protein trafficking and likely expression, we are investigating possible interactions between htt-interacting proteins and actin-binding proteins. Specifically, the htt-interacting protein HIP1 and actin-crosslinking proteins such as α-actinins contain putative interacting modular domains. Studies in transfected HEK cells suggest the two proteins bind each other (Fan et al., Prog#92.9, SFN 32nd Annual Meeting 2002). Furthermore, fractionation of cortical and striatal tissues from FVB/N mi...