Project 467232

Disruption of synaptic communication by genetic disorders, aging, viral infections, and other agents is one of the leading underlying causes of brain disorders, such as Alzheimer's disease, intellectual disabilities, and schizophrenia. Synaptic communication is particularly influenced by a post-translational protein modification called palmitoylation, which is critical for the regulation of protein trafficking and cell signalling. Roughly 41% of all synaptic proteins are tagged by palmitoylation, and the process is highly dynamic and heavily involved in the regulation of synapse formation and function. This is highly relevant as mutations in palmitoylating enzymes have been linked with the aforementioned brain disorders. Loss of function mutations in one of these enzymes, zDHHC9, have been specifically linked with X-linked intellectual disability and epilepsy. Previous experiments from the Bamji lab have shown zDHHC9 necessary for proper anatomical development of neurons grown in cell culture and revealed how loss of function of zDHHC9 in an animal model can lead to cognitive defects and epileptic comorbidities. Building on these findings, this project will further explore how loss of function of zDHHC9 impacts structural and functional neuroanatomy in the intact animal and which proteins exhibit altered palmitoylation when zDHHC9 is non-functional. The proposed research will thus help to fill a large gap in our understanding of the role of palmitoylating enzymes in brain development, the anatomical changes that contribute to patient symptoms, and the molecular targets of palmitoylation. This is especially important as it may soon become possible to therapeutically regulate palmitoylation and its downstream targets with recent advances in genetic and drug technologies.