Grant: Project Grant

Schizophrenia is a serious mental illness that affects 1% of the population and costs Canadians >$2 billion a year. The brains of schizophrenics are fundamentally different than people who don't have the disorder, and researchers believe that this arises during brain development. Indeed, it is now thought that deficits in brain cell connectivity as well as chemical imbalances can manifest as symptoms of schizophrenia. We believe that a chemical process called 'palmitoylation' plays a critical role in the development and functioning of the brain, and that disrupting this chemical process can produce some of the perturbations observed in the brains of schizophrenic patients. In particular, we have focused on the enzyme, DHHC5, which we hypothesize is positioned in a signaling 'hub' that is disrupted in some patients with schizophrenia. This proposal follows our demonstration that DHHC5 plays a critical role in regulating brain cell connectivity in cultured cells. While there is clearly a genetic component to schizophrenia, many different genes have been associated with the disorder and no single gene has been found responsible for, or predictive of, schizophrenia. However, 9 of the 23 genes that encode palmitoylating enzymes (DHHCs) have been associated with disorders of the brain [1] and a mutation in DHHC5 that impairs the regulation of this enzyme has been identified in a schizophrenic patient [2-4]. Moreover, a recent study has shown that ~67% of all genes associated with schizophrenia encode proteins that are substrates for palmitoylation [5]. Together, this underscores the importance of studying palmitoylation in brain development and phenotypes associated with schizophrenia. Using neurons grown in culture as well as transgenic mouse models, we will determine whether DHHC5 malfunction leads to aberrant brain development and behaviors associated with schizophrenia, and whether targeting this pathway is a viable therapeutic option to normalize brain health.