Palmitoylation in the Pathogenesis of Huntington Disease

Huntington disease (HD) is a devastating inherited neurological disease characterized by loss of motor control, cognitive decline and psychiatric disturbances, resulting in eventual death 15 to 20 years after symptoms first appear. In Canada, one in 10,000 people have Huntington disease, and have a 50 per cent risk of passing on the disease to their children. The underlying genetic cause of HD is an expansion of a specific portion of the HD gene, known as the CAG trinucleotide repeat, which results in an expanded stretch of an amino acids in the huntingtin protein. This expansion leads to cell death in specific parts of the brain through mechanisms that are the subject of intense investigation. When the HD gene is translated into huntingtin, the protein undergoes alterations at many sites. Palmitoylation is an example of such an alteration, which involves the addition of a small fatty-acid chain to a protein. Palmitoylation enhances the ability of a protein to associate with membranes (e.g. cell walls), and influences that protein’s trafficking and function. Most notably, palmitoylation is a reversible protein modification. Decreased palmitoylation may play a role in the cellular events underlying the development of HD. Fiona Young is investigating the role of palmitoylation in the development of Huntington Disease as well as in the context of the normal function of the huntingtin protein. The research could lead to new therapeutic approaches for Huntington disease that involve increasing palmitoylation of the huntingtin protein.