Figure 7. Proposed model for impairment of the HSR in HD.

Disease pathogenesis in HD leads to a progressive reduction in levels of Tetra AcH4 at HS promoters (i), possibly as a consequence of reduced histone acetyl transferase (HAT) activity. Reduced levels of Tetra AcH4 impair the ability of HSF1 to bind its target consensus sequences at HS genes (ii). Reduced HSF1 binding leads to reduced release and recruitment of RNA polymerase 2 (iii), which in turn results in an inability to efficiently upregulate HSPs (iv). Impairment of the HSR may be augmented by reduced H4 acetylation and nucleosome displacement as a consequence of impairment of HSF1 binding, RNA polymerase 2 release and/or recruitment, and association of other factors (e.g., PARP) (vi and vii). As a consequence, cells become vulnerable to acute proteotoxic stress, thereby accelerating disease progression (v).