Hip14l-deficient mice develop neuropathological and behavioural features of Huntington disease

Abstract

Palmitoylation, the dynamic post-translational addition of the lipid, palmitate, to proteins by Asp-His-His-Cys-containing palmitoyl acyltransferase (PAT) enzymes, modulates protein function and localization and plays a key role in the nervous system. Huntingtin-interacting protein 14 (HIP14), a well-characterized neuronal PAT, has been implicated in the pathogenesis of Huntington disease (HD), a fatal neurodegenerative disease associated with motor, psychiatric and cognitive symptoms, caused by a CAG expansion in the huntingtin gene (HTT). Mice deficient for Hip14 expression develop neuropathological and behavioural features similar to HD, and the catalytic activity of HIP14 is impaired in HD mice, most likely due to the reduced interaction of HIP14 with HTT. Huntingtin-interacting protein 14-like (HIP14L) is a paralog of HIP14, with identical domain structure. Together, HIP14 and HIP14L are the major PATs for HTT. Here, we report the characterization of a Hip14l-deficient mouse model, which develops adult-onset, widespread and progressive neuropathology accompanied by early motor deficits in climbing, impaired motor learning and reduced palmitoylation of a novel HIP14L substrate: SNAP25. Although the phenotype resembles that of the Hip14(-/-) mice, a more progressive phenotype, similar to that of the YAC128 transgenic mouse model of HD, is observed. In addition, HIP14L interacts less with mutant HTT than the wild-type protein, suggesting that reduced HIP14L-dependent palmitoylation of neuronal substrates may contribute to the pathogenesis of HD. Thus, both HIP14 and HIP14L may be dysfunctional in the disease.

The Canonical DHHC Motif Is Not Absolutely Required for the Activity of the Yeast S-acyltransferases Swf1 and Pfa4

“…It should be noted that all three proteins are fully acylated in the presence of WT Swf1, and no acylation is detectable for swf1⌬ strains. develop neuropathological and behavioral features of Huntington disease (41), and mice with a nonsense mutation in this gene present with alopecia, osteoporosis, and systemic amyloidosis (42). Most other PATs with the divergent DHHC motif that we identified have not yet been studied.…”

Mechanism and function of DHHC S-acyltransferases

“…In many cases, subsequent DHHC gene silencing experiments have confirmed the assignment of a cognate enzyme-substrate pair [34]. Characterization of DHHCknockout mouse models has also been informative in assigning substrates [35][36][37].…”

Fatty acylation of proteins: The long and the short of it

“…Studies of mice with loss of function alleles or knockout of a single DHHC gene have uncovered distinct phenotypes [61]. For example, mice deficient in DHHC13 or DHHC17 exhibit neurological defects similar to Huntington disease [64, 65], while defects in vascular tone and hair follicle differentiation result when mice produce non-functional DHHC21 [66, 67]. …”