Grant: Project Grant

Intellectual disability (ID) is characterized by poor general mental capacity, such as learning, reasoning and problem solving, and is caused by disruptions in the proper development of the brain. Severe ID is almost always accompanied by other neurological challenges including epilepsy, speech defects and autism. There is a clear genetic component to ID; patients with ID often have mutations in genes that code for proteins that control the structure of the neuron (nerve cell), the formation of synapses (connections between neurons where information is exchanged), or the formation and breakdown of synapse proteins. Studies have clearly demonstrated that even minor disruptions in synapse structure and function can give rise to mild to severe changes in intellectual abilities. There is growing evidence that a chemical process called 'palmitoylation', in which palmitic acid is attached to proteins, may play a central role in the proper development and functioning of synapses. Mutations in enzymes that mediate palmitoylation, called ZDHHC enzymes, have been linked to a number of neurodevelopmental disorders including schizophrenia, autism, and ID. Interestingly, nearly 2% of all patients who have ID linked to the X chromosome have mutations in ZDHHC9 (one of 23 known ZDHHC enzymes). The large majority of patients with ZDHHC9 mutations also have epilepsy, underscoring a link between, ID and epilepsy. In this proposal we will: 1) evaluate the role of ZDHHC9 in controlling the proper formation of neurons and synapses as well as support cells called oligodendrocytes; 2) identify all synaptic proteins that can be modified by ZDHHC9; and 3) determine whether reintroducing ZDHHC9 into the brains of juvenille mice that lack this enzyme can rescue some of the structural and behavioral deficits seen in these animals. This work will establish whether ZDHHC9 is a viable target for the development of therapeutics to treat patients with ID.