IngentaConnect Huntingtin's WW domain partners in Huntington's disease post-mort...

Authors: Passani, Lucius A.; Bedford, MarkT.¹; Faber, PeterW.; McGinnis, Kim M.; Sharp, AlanH.²; Gusella, JamesF.; Vonsattel, Jean-Paul³; MacDonald, Marcy E.

Source: Human Molecular Genetics, Volume 9, Number 14, 1 September 2000 , pp. 2175-2182(8)

Publisher: Oxford University Press

Abstract:

An elongated glutamine tract in mutant huntingtin initiates Huntington’s disease (HD) pathogenesis via a novel structural property that displays neuronal selectivity, glutamine progressivity and dominance over the normal protein based on genetic criteria. As this mechanism is likely to involve a deleterious protein interaction, we have assessed the major class of huntingtin interactors comprising three WW domain proteins. These are revealed to be related spliceosome proteins (HYPA/FBP-11 and HYPC) and a transcription factor (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 not with filter trapped insoluble-aggregate. Glutathione S-transferase partner ‘pull-down’ assays reveal soluble, aberrantly migrating, forms of full-length mutant huntingtin specific to HD target tissue. Importantly, these novel mutant species exhibit exaggerated WW domain binding that abrogates partner association with other huntingtin isoforms. Thus, each WW domain partner’s association with huntingtin fulfills HD genetic criteria, supporting a direct role in pathogenesis. Our findings indicate that modification of mutant huntingtin in target neurons may promote an abnormal interaction with one, or all, of huntingtin’s WW domain partners, perhaps altering ribonucleoprotein function with toxic consequences.

Document Type: Research article

Affiliations: 1: Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115, USA and 2: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 3: Laboratory for Molecular Neuropathology, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA,

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