This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion in the huntingtin protein. It was suggested that the longer polyglutamine domain induce conformational changes, causing it to form intracellular aggregates as nuclear inclusions in most cases. HD is characterized by disturbances in motor, cognitive and psychiatric function. It has been postulated that the expanded polyglutamine repeat causes huntingtin to interact abnormally with other cellular proteins. Wild-type huntingtin was found to interact with the transcriptional regulator REST which represses most neuronal gene expression in non-neuronal cells. The interaction between huntingtin and REST kept REST in the cytosol, thereby preventing REST target genes repression. It was shown that wild-type and mutant huntingtin mediate REST dependent neuronal gene expression of BDNF through its regulatory DNA element RE1. We have cloned another REST interacting protein we called RILP for REST/NRSF-Interacting LIM domain Protein. RILP is a novel protein which is required for the nuclear targeting and function of REST. We have preliminarily identified another RILP-interacting protein, which is dynactin p150Glued, and have shown that huntingtin and dynactin p150Glued copurify with RILP. Dynactin p150Glued is an accessory protein for the microtubule motor protein dynein which is thought to be involved in trafficking steroid receptors and some other transcription factors between the cytoplasm and nucleus in a dynactin dependent process. We thus postulate that RILP, dynactin p150Glued, and huntingtin are involved in targeting cytoplasmically synthesized REST through the dynein-microtubule pathway to the nucleus. Disruption of this function could contribute to the neuronal dysfunction and death seen in diseases, such as Huntington's disease (HD).
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