Butland, Stefanie L.

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.

Post-translational modification of proteins by the lipid palmitate is critical for protein localization and function. Palmitoylation is regulated by the opposing enzymes palmitoyl acyltransferases (PATs) and acyl protein thioesterases, which add and remove palmitate from proteins, respectively. Palmitoylation is particularly important for a number of processes including neuronal development and synaptic activity in the central nervous system. Dysregulated palmitoylation contributes to neuropsychiatric disease. In total six PATs (HIP14, HIP14L, ZDHHC8, ZDHHC9, ZDHHC12, and ZDHHC15) and one thioesterase (PPT1) have been implicated in Huntington disease (HD), Alzheimer disease, schizophrenia, mental retardation, and infantile and adult onset forms of neuronal ceroid lipofuscinosis. Currently there is no genetic link between PATs and Alzheimer disease pathogenesis but palmitoylation of amyloid precursor protein-processing enzyme, γ-secretase, influences β-amyloid generation. Several lines of evidence point to a role for palmitoylation by HIP14 in the pathogenesis of HD; HIP14 is dysfunctional in the presence of the HD mutation and Hip14-deficient mice develop features of HD. Wildtype huntingtin (the protein mutated in HD) enhances the PAT activity of HIP14 and mutant HTT interacts less with HIP14. Therefore, it may be that loss of the positive modulation of HIP14 activity due to reduced interaction with huntingtin is important in the disease mechanism. Preliminary evidence suggests a closely related PAT to HIP14, HIP14L, may also play a role in the pathogenesis of HD. In order to design rational therapeutic approaches to restore palmitoylation in neuropsychiatric disease, it will be critical to better understand the relationships between PATs and thioesterases with their regulators and substrates.