The role of altered palmitoylation of synaptic proteins in synaptic function/dysfunction in a mouse model of Huntington’s disease

Within each individual cell, different proteins are localized to specific and necessary locations. There are many different ways these proteins are directed to where they need to go. One method for influencing protein localization is palmitoylation, which is the addition of a lipid molecule, specifically palmitate, to the protein. Protein localization is especially important in neurons, where synaptic proteins need to be carefully organized and localized to the pre- and post-synaptic regions of the neuron in order to accurately convey messages from one neuron to another. In Huntington's disease, which is characterized by neuronal death and subsequent severe motor and cognitive disturbances, it appears that synaptic proteins are mis-localized outside of the synapse, which causes synaptic dysfunction prior to cell death and symptom onset. Preventing this early synaptic dysfunction is believed to be a viable means of preventing or significantly delaying cell death and Huntington’s disease symptoms. Previous work has suggested that the level of palmitoylation is decreased in Huntington’s disease and that this may contribute to early synaptic protein dysfunction. Dr. Matthew Parsons is working to determine how the palmitoylation of specific synaptic proteins regulates their localization within the synapse and how this relates to the synaptic dysfunction observed in Huntington’s disease. Specifically, he is using different techniques to compare the properties of synaptic communication, synaptic protein localization and neuronal vulnerability to cell death in mice that have Huntington’s disease and mice with reduced protein palmitoylation. He will also use neuronal cultures from wild-type animals to investigate the effects of experimentally manipulated protein palmitoylation. Should the synaptic dysfunction due to decreased palmitoylation resemble the synaptic dysfunction in Huntington’s disease, he will also attempt to rescue the early Huntington’s disease phenotype by overexpression of a protein known to promote palmitoylation. These studies will help determine whether the regulation of synaptic protein palmitoylation may be a viable target for the treatment of Huntington’s disease.