Huntingtin's WW domain partners in Huntington's disease post-mortem brain fulfill genetic criteria for direct involvement in Huntington's disease pathogenesis

An elongated glutamine tract in mutant huntingtin initiates Huntington's di sease (HD) pathogenesis via a novel structural property that displays neuro nal selectivity, glutamine progressivity and dominance over the normal prot ein based on genetic criteria, As this mechanism is likely to involve a del eterious protein interaction, we have assessed the major class of huntingti n interactors comprising three WW domain proteins. These are revealed to be related spliceosome proteins (HYPA/FBP-11 and HYPC) and a transcription fa ctor (HYPB) that implicate huntingtin in mRNA biogenesis, In HD post-mortem brain, specific antibody reagents detect each partner in HD target neurons , in association with disease-related N-terminal morphologic deposits but n ot with filter trapped insoluble-aggregate. Glutathione S-transferase partn er 'pull-down' assays reveal soluble, aberrantly migrating, forms of full-l ength mutant huntingtin specific to HD target tissue, Importantly, these no vel mutant species exhibit exaggerated WW domain binding that abrogates par tner association with other huntingtin isoforms, Thus, each WW domain partn er's association with huntingtin fulfills HD genetic criteria, supporting a direct role in pathogenesis. Our findings indicate that modification of mu tant huntingtin in target neurons may promote an abnormal interaction with one, or all, of huntingtin's WW domain partners, perhaps altering ribonucle oprotein function with toxic consequences.