Regulation of the structural dynamics, aggregation, and pathogenicity of polyQ-expanded Huntingtin by osmolytes

Huntington Disease is an autosomal dominant neurodegenerative disease caused by expansion of the polymorphic trinucleotide CAG repeat of the HTT gene to code for an expanded glutamine track of the mutant Huntingtin protein (mHTT). Like other neurodegenerative diseases, symptomatic presentation of Huntington Disease is age-dependent or age-related. This age-dependent manifestation of an autosomal dominant disease trait underscores important and possibly priming role of age-related changes in cellular physiology that are conducive to disease presentation. Herein, we present studies on the effects of osmolytes on mHTT structuring and aggregation, vis-a-vis pathogenicity. We show that stabilizing polyol osmolytes, by their generic activity in promoting protein structuring and compaction, drive aggregation of the disordered mHTT protein and simultaneously inhibit their binding to and sequestration of key transcription factors for improved homeostasis and cell survival under stress. These and related observations in the literature give strong support to the notion that lower molecular weight and structurally dynamic forms of mHTT contribute importantly to disease pathogenesis. Aging is associated with important changes in the cell environment-disease protein accumulation, reduced hydration, and macromolecular crowding as examples. These changes have significant consequences on the structuring and pathogenicity of the disordered mHTT protein. A crowded and less hydrated aging cell environment is conducive to mHTT binding to and inhibition of cell regulatory protein function on the one hand, and in promoting mHTT aggregation on the other hand, to culminate in Huntington disease presentation.