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The role of palmitoylation in the pathogenesis of Huntington disease Sanders, Shaun Samantha Fancey

Abstract

Huntington disease (HD) is caused by a CAG expansion in HTT characterized by motor, cognitive, and psychiatric disturbances. Huntingtin Interacting Protein 14 (HIP14) and HIP14-like (HIP14L) are palmitoyl acyltransferases (PATs) that mediate the post-translational addition of fatty acids to proteins (palmitoylation). They palmitoylate HTT and have reduced interaction with and palmitoylation of mutant HTT (mHTT), leading to increased mHTT inclusion formation and toxicity. HTT is essential for full enzymatic activity of HIP14 and loss of either of these genes leads to HD-like phenotypes. The goal was to determine the role of palmitoylation in the pathogenesis of HD. The overall hypothesis is that disturbed HIP14- and HIP14L-HTT interaction in HD reduces PAT function leading to the under-palmitoylation and mislocalization of HTT and key HIP14 and HIP14L substrates. Multiple putative PAT binding sites in HTT were identified, one around aa224 and one around aa427, that are required for full interaction but aa1-548 are required for the structural integrity of the binding sites. Loss of both Hip14 and Hip14l leads to embryonic lethality between day 10 and 11 in utero, due to failed placenta formation. Intriguingly, the extraembryonic tissue of Hip14-/-;Hip14l-/- embryos share many features with that of Htt-/- embryos and palmitoylation of HTT was decreased by 25% in Hip14-/-;Hip14l-/- mouse embryonic fibroblasts. Palmitoylation of mHTT, SNAP25, and PSD-95 was decreased in the YAC128, BACHD, and Hu97/18 mouse models of HD. The HD-like phenotype of the Hip14-/- mice is developmental and non-progressive, unlike the adult-onset, progressive phenotype of the YAC128 mice. Mice in which Hip14 deficiency is induced in adulthood show reduced survival, motor deficits, anhedonia, increased escape response, increased forebrain weight and cortical volume, and decreased corpus callosum volume. This indicates that loss of Hip14 from conception allows for developmental compensation that cannot occur if Hip14 deficiency occurs in the adult.

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