Polyglutamine Flanking Regions in Huntingtin Highlight Key Structural Intermediates Relevant for Molecular Chaperone Interaction and Huntington's Disease Pathogenesis

Huntington's Disease (HD) is a neurodegenerative disorder caused by an expansion in the polyglutamine (polyQ) tract of the Huntingtin (Htt) protein. The clinical hallmark of this mutation is the accumulation of amyloid Htt aggregates in neurons. While Htt aggregation is highly correlated with the length of this polyQ tract both in vitro and in vivo, recent studies suggest that the regions flanking the polyQ tract can influence Htt aggregation and toxicity independent of polyQ length. In addition, it is well established that two polyQ flanking regions in exon1 of Htt, the N-terminal first 17 amino acids (N17) and a proline-rich region (PolyPro), influence Htt aggregation propensity. Here, we show that the N17 and PolyPro regions of Htt dramatically influence the rate of the Htt aggregation pathway. We also show that mutations within these polyQ-flanking regions alter Htt toxicity in a brain slice model. The influence of these flanking regions on the heterogeneous distribution of the aggregate species may account for these differences in toxicity. This theory is increasingly relevant in light of recent thought that Htt toxicity may derive from a species other than the amyloid fibril itself. Finally, previous work has shown that the N17 region of Htt interacts with the molecular chaperonin TRiC, and this interaction exerts a protective effect against both Htt aggregation and toxicity. An understanding how these flanking regions influence Htt aggregation will inform how TRiC works through the N17 element. Together, this information can provide the basis to design HD therapeutics that exploit these flanking regions to suppress HD pathogenesis.