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

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.

Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry

“…Another interesting set of GO categories populated by upregulated genes was categories associated with RNA splicing/RNA processing. This is particularly intriguing given that mutant and wild-type huntingtin have been reported to have differential affinities for WW-domain proteins involved in RNA splicing (Passani et al, 2000).…”

Prp40 pre-mRNA processing factor 40 homolog B (PRPF40B) associates with SF1 and U2AF65and modulates alternative pre-mRNA splicing in vivo

“…Based on the Prp40 data, PRPF40A and PRPF40B are thought to participate in early spliceosome assembly, but their functions remain unknown. Notably, PRPF40B has been implicated in the pathogenesis of neurological disorders, including Huntington's disease and Rett syndrome (Faber et al 1998;Passani et al 2000;Buschdorf and Strätling 2004). Moreover, mutations in spliceosome components involved in splice site recognition have been recently detected in myelodysplastic syndrome (MDS), a group of disorders that lead to myeloid leukemia (Papaemmanuil et al 2011;Yoshida et al 2011).…”

Huntingtin Bodies Sequester Vesicle-Associated Proteins by a Polyproline-Dependent Interaction

“…The role of mutant htt aggregates in cell death is controversial, because the presence of aggregates does not consistently correlate with cell death (Saudou et al, 1998;Sisodia 1998;Kim et al, 1999;Kuemmerle et al, 1999). A soluble, nonaggregated, mutant htt might contribute to neurodegeneration by engaging in abnormal protein interactions (Bao et al, 1996;Sittler et al, 1998;Passani et al, 2000;Gervais et al, 2002). Oligomers of mutant htt expressed from exon 1 form spheroids and protofibrils as intermediates (prefibrillar forms) during fibril assembly (Poirier et al, 2002).…”