Huntington’s disease arises from CAG codon-repeat expansions in the Htt gene, which leads to a Htt gene
product with an expanded polyglutamine (polyQ) sequence. The length of the polyQ expansion correlates with an increased
tendency to form aggregates and clustering into micrometer-plus sized inclusion bodies in neurons and other cell
types. Yet after nearly 20 years since the genetic basis for HD was identified, our knowledge of how polyQ-expanded Htt
fragment aggregation relates to disease mechanisms remains fragmentary and controversial. Challenges remain in defining
the aggregation process at the molecular level and how this process is influenced by, or influences cellular activities.
Insight is further confounded by the term “aggregation” being used to describe a composite of distinct processes that may
have opposing consequences to cell health and survival. This review discusses these issues in light of a historic summary
of Htt aggregation in the cellular milieu and the intrinsic attributes of polyQ-expanded Htt that lead to aggregation. Finally,
discussion centers on strategies forward to improve our knowledge for how aggregation relates to cellular dysfunction.
Keywords: Huntington’s disease (HD), huntingtin, polyglutamine (polyQ), misfolding, aggregation
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