Aberrant palmitoylation in Huntington disease
Related Experiment Video
Updated: Apr 15, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Shaun S Sanders1, Michael R Hayden1
1*Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
Insights
Huntington disease (HD) may stem from altered palmitoylation. The huntingtin (HTT) mutation disrupts interactions with HIP14/HIP14L, reducing protein palmitoylation and causing neuronal toxicity.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington disease (HD) is an inherited neurodegenerative disorder.
- It is caused by a CAG expansion in the huntingtin (HTT) gene, leading to striatal atrophy and motor, cognitive, and psychiatric symptoms.
Purpose of the Study:
- To investigate the role of huntingtin interacting protein 14 (HIP14) and HIP14-like (HIP14L) in Huntington disease pathogenesis.
- To explore the impact of the HD mutation on HTT palmitoylation and the activity of HIP14/HIP14L.
Main Methods:
- Examining the interactions between huntingtin (HTT) and huntingtin interacting protein 14 (HIP14/DHHC17) and HIP14-like (HIP14L/DHHC13).
- Analyzing the effects of genetic ablation of Hip14 or Hip14l on HD-like phenotypes in mouse models.
- Investigating changes in HTT palmitoylation and the activity of HIP14/HIP14L in the presence of the HD mutation.
Main Results:
- Genetic deletion of Hip14 or Hip14l recapitulated HD features like striatal atrophy and motor deficits.
- While HTT palmitoylation was unchanged in Hip14/Hip14l knockout models, phenotypes suggested underpalmitoylation of other substrates.
- The HD mutation was found to reduce HIP14 activity, leading to decreased palmitoylation of HIP14 substrates and neuronal toxicity.
Conclusions:
- Altered interactions between mutant HTT and HIP14/HIP14L reduce protein palmitoylation.
- This reduction in palmitoylation affects the localization of HTT and other HIP14/HIP14L substrates.
- Huntington disease may be, in part, a disease characterized by altered protein palmitoylation.
Abstract:
Huntington disease (HD) is an adult-onset neurodegenerative disease caused by a CAG expansion in the HTT gene. HD is characterized by striatal atrophy and is associated with motor, cognitive and psychiatric deficits. In the presence of the HD mutation, the interactions between huntingtin (HTT) and huntingtin interacting protein 14 (HIP14 or DHHC17) and HIP14-like (DHHC13, a HIP14 orthologue), palmitoyl acyltransferases for HTT, are disturbed, resulting in reduced palmitoylation of HTT. Genetic ablation of either Hip14 or Hip14l recapitulates many features of HD, including striatal atrophy and motor deficits. However, there are no changes in palmitoylation of HTT in either mouse model and, subsequently, the similarities between the phenotypes of these two mouse models and the HD mouse model are believed to result from underpalmitoylation of other HIP14 and HIP14L substrates. HTT acts as a modulator of HIP14 activity such that in the presence of the HD mutation, HIP14 is less active. Consequently, HIP14 substrates are less palmitoylated, leading to neuronal toxicity. This suggests that altered HIP14-HTT and HIP14L-HTT interactions in the presence of the HD mutation reduces palmitoylation and promotes mislocalization of HTT and other HIP14/HIP14L substrates. Ultimately, HD may be, in part, a disease of altered palmitoylation.
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