Discovery of a Novel Aggregation Domain in the Huntingtin Protein: Implications for the Mechanisms of Htt Aggregation and Toxicity

摘要

Huntington's Disease (HD) is caused by CAG trinucleotide expansion, which translates to polyQ repeats, within exonl of the Htt gene, which encodes for the Huntingtin (Htt), a 350 kDa protein (Figure 1 A) that is highly expressed in the brain and different organs. In HD-affected people, the length of the polyQ repeat varies from 36-120 residues, with a length of 42-50 residues being associated with adult onset, and a length of over 60 residues associated with juvenile onset. Although the mechanisms by which the expanded polyQ contribute to Htt-induced toxicity remain unknown, the formation of nuclear inclusions of Htt in the brain of HD patients is an invariant feature and thought to contribute to disease pathogenesis by a gain-of-toxic-function and partial loss of normal function linked to the polyQ mediated Htt aggregation.