Genetic expansion of polyglutamine (polyQ) domains is associated with disease risk and protein deposition in Huntington’s disease (HD) and a family of related disorders. In HD, fragments of mutant huntingtin (Htt) protein misfold and aggregate, with these processes considered to be important pathogenic factors relevant to disease onset and propagation. In our structural studies enabled by advanced solid-state NMR spectroscopy and electron microscopy, we have developed structural models of the aggregates and proposed mechanistic implications for the aggregation processes leading to their formation. By combining structural insights with kinetics analyses, we study the mechanism by which the mutant proteins undergo pathogenic aggregation in HD. Notably, different Htt domains, as well as environmental factors, modulate the kinetics of deposition and also dictate the structure and characteristics of distinct types of polymorphic deposits. Interestingly both primary and secondary nucleation events are instrumental in the self assembly of mutant huntingtin exon 1. With the aid of integrated structural studies, we endeavor to gain insight into the molecular and conformational factors that dictate these pathogenic pathways. These molecular events relate to disease onset and disease propagationin vivo, based on the characteristic ability of the aggregates to recruit as-yet undeposited proteins into the assembly. Thus kinetic and structural models can facilitate the rational design of potential inhibitors or modulators. On a more fundamental level, in-depth studies of the behavior of these kinds of polymorphic proteins and the role of various types of amyloidogenic nucleation events provides important new insight into the complex folding landscape of polypeptides and the role of both protein-protein and protein-solvent interactions.

Molecular aspects of primary and secondary nucleation in antiparallel polyglutamine amyloid formation in Huntington’s disease

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.