Analysis of the substrate network and neurodevelopmental functions of the intellectual disability enzyme, zDHHC9

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Development of new treatments and cures for cognitive and psychiatric disorders requires a detailed understanding of the underlying biological perturbations that cause these conditions. Although similar neurological conditions can be caused by a large array of different gene mutations, it is likely that these disorders develop due to disruption of common cellular pathways. Mutations in the ZDHHC9 gene, which encodes an enzyme that attaches fats onto cellular proteins, causes intellectual disability, seizures, and speech and attention problems. Furthermore, mutations in this gene also perturb the corpus callosum, a brain region that mediates communication between the two sides of the brain, and which is disrupted in a range of neurodevelopmental disorders. The aim of this grant is to use a mouse model lacking Zdhhc9 to investigate the molecular and cellular changes that might lead to the neurological deficits seen in humans with ZDHHC9 mutations. Specifically, we will determine how loss of Zdhhc9 leads to disruption of the corpus callosum and identify key substrates of this enzyme that are linked to deficits in this brain region. Furthermore, we will assess if Zdhhc9 mutant mice exhibit the full spectrum of behavioural changes seen in humans with ZDHHC9 mutations by investigating oromotor and attention behaviours in these mice. In addition to providing new insight into how ZDHHC9 mutations disrupt brain function, this new knowledge may also improve our understanding of more common neurological disorders in the general population.