A HUNTINGTIN-ASSOCIATED PROTEIN ENRICHED IN BRAIN WITH IMPLICATIONS FOR PATHOLOGY

HUNTINGTON'S disease (HD) is an autosomal dominant neurodegenerative d isorder caused by an expanding polyglutamine repeat in the IT15 or hun tingtin gene(1). Although this gene is widely expressed(2-9) and is re quired for normal development(10-12), the pathology of HD is restricte d to the brain, for reasons that remain poorly understood. The hunting tin gene product is expressed at similar levels in patients and contro ls, and the genetics of the disorder(13,14) suggest that the expansion of the polyglutamine repeat induces a toxic gain of function, perhaps through interactions with other cellular proteins(15-18). Here we rep ort the identification of a protein (huntingtin-associated protein (HA P)-1) that binds to huntingtin. This binding is enhanced by an expande d polyglutamine repeat, the length of which is also known to correlate with the age of disease onset(19-21). The HAP-1 protein is enriched i n the brain, suggesting a possible basis for the selective brain patho logy of HD.