Abstract
Polyglutamine expansion in the huntingtin protein is the primary genetic cause of Huntington’s disease (HD). Fragments coinciding with mutant huntingtin exon1 aggregate in vivo and induce HD-like pathology in mouse models. The resulting aggregates can have different structures that affect their biochemical behaviour and cytotoxic activity. Here we report our studies of the structure and functional characteristics of multiple mutant htt exon1 fibrils by complementary techniques, including infrared and solid-state NMR spectroscopies. Magic-angle-spinning NMR reveals that fibrillar exon1 has a partly mobile α-helix in its aggregation-accelerating N terminus, and semi-rigid polyproline II helices in the proline-rich flanking domain (PRD). The polyglutamine-proximal portions of these domains are immobilized and clustered, limiting access to aggregation-modulating antibodies. The polymorphic fibrils differ in their flanking domains rather than the polyglutamine amyloid structure. They are effective at seeding polyglutamine aggregation and exhibit cytotoxic effects when applied to neuronal cells.
Highlights
Polyglutamine expansion in the huntingtin protein is the primary genetic cause of Huntington’s disease (HD)
Huntington’s Disease (HD) is the most prevalent example of a family of neurodegenerative diseases that have the abnormal expansion of a polyglutamine stretch as their primary genetic cause[1]
To understand exon[1] aggregate polymorphism, the exon[1] aggregation mechanism, and how both can be modulated by htt exon1-binding proteins and post-translational modifications (PTMs), it is crucial to know the structure of the aggregated species
Summary
Polyglutamine expansion in the huntingtin protein is the primary genetic cause of Huntington’s disease (HD). It is increasingly recognized that cells contain different types of aggregates, including fibrillar aggregates that are not as detected as large inclusions[3,4,5] Such polymorphism is reminiscent of other amyloids[6,7], and is important, given that the toxicity of htt exon[1] aggregates is known to depend on their structure[8,9]. We refer to these httNTQ30P10K2 peptides (Fig. 1b) as HNTFs. A recent ssNMR study on fibrils prepared using thioredoxin-fused htt exon[1] failed to detect the signals for an a-helical httNT, raising the possibility that httNT has a different structure in fibrillar exon[1] In detectable changes, not in the polyQ as previously suggested, but rather in the non-amyloid flanking domains
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