Amyloid formation by mutant huntingtin: Threshold, progressivity and recruitment of normal polyglutamine proteins

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat encoding a tract of consecutive glutamines near the amino terminus of hunt ingtin, a large protein of unknown function. It has been proposed that the expanded polyglutamine stretch confers a new property on huntingtin and the reby causes cell and region-specific neurodegeneration. Genotype-phenotype correlations predict that this novel property appears above a threshold len gth (similar to 38 glutamines), becomes progressively more evident with inc reasing polyglutamine length, is completely dominant over normal huntingtin and is not appreciably worsened by a double genetic dose in ND homozygotes . Recently, an amino terminal fragment of mutant huntingtin has been found to form self-initiated fibrillar aggregates in vitro. We have tested the ca pacity for aggregation to assess whether this property matches the criteria expected for a fundamental role in ND pathogenesis. We find that that in v itro aggregation displays a threshold and progressivity for polyglutamine l ength remarkably similar to the HD disease process. Moreover the mutant hun tingtin amino terminus is capable of recruiting into aggregates normal glut amine tract proteins, such as the amino terminal segments of both normal hu ntingtin and of TATA-binding protein (TBP). Our examination of in vivo aggr egates from HD post-mortem brains indicates that they contain an amino term inal segment of huntingtin of between 179 and 595 residues. They also conta in non-huntingtin protein, as evidenced by immunostaining for TBP Interesti ngly, like the in vitro aggregates, aggregates from ND brain display Congo red staining with green birefringence characteristic of amyloid. Our data s upport the view that the expanded polyglutamine segment confers on huntingt in a new property that plays a determining role in HD pathogenesis and coul d be a target for treatment. Moreover the new property might have its toxic consequences by interaction with one or more normal polyglutamine-containi ng proteins essential for the survival of target neurons.