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

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.

Mutations in the ZDHHC9 gene cause intellectual disability, epilepsy, hypotonia, and speech and attention deficits. These physiological changes are accompanied by hypoplasia of the corpus callosum, a brain region that connects the cerebral hemispheres. ZDHHC9 encodes an enzyme that mediates S-acylation, an important post-translational modification of intracellular proteins. We have investigated the effects of knocking out (KO) Zdhhc9 in mice. Analyses of these mice uncovered learning and memory deficits and hypotonia, consistent with the phenotype of humans with ZDHHC9 mutations. In addition, the mice exhibit anxiety changes that are common in other mouse models of intellectual disability. Furthermore, MRI-based volumetric analysis showed that the corpus callosum is reduced by 36% in Zdhhc9 KO mice compared to their wild-type littermates. Overall, these findings provide compelling evidence supporting the utility of the Zdhhc9 KO mice to investigate molecular and cellular changes that lead to neurological impairments in humans. With this in mind, the aims of this project are to: (i) identify cellular and molecular changes underlying corpus callosum hypoplasia in KO mice; (ii) identify the brain substrate network of zDHHC9, and pinpoint substrates linked to corpus callosum hypoplasia; and (iii) determine if the KO mice exhibit the full spectrum of deficits seen in humans with ZDHHC9 mutations by analysing oromotor and attention behaviour.
Addressing these aims will provide new insight into the molecular and cellular pathways linked to intellectual disability and other neurodevelopmental deficits in humans with ZDHHC9 mutations, and may also unveil novel pathways that are disrupted in similar but more common neurological disorders.

The results of this project grant will not only benefit academics but will also impact the commercial and healthcare sectors, charities and the general public. Specifically, we will make important molecular and cellular breakthroughs that will increase knowledge of how loss of function of zDHHC9 leads to intellectual disability, epilepsy, and speech and attention deficits. The results of these analyses are likely to attract interest and potentially investment from pharmaceutical companies searching for new therapies and treatments for these important neurodevelopmental conditions. The work will similarly be of interest to clinicians working on these disorders. The time-scale for these impacts is short-term (within the time-frame of the grant or shortly thereafter).

A longer-term impact (10-15 years) may be on people affected by intellectual disability, epilepsy, and/or speech and attention problems if our study contributes to the development of new treatments and therapies. Other short-term beneficiaries of the research will be relevant charities (who we communicate with via Twitter) and the general public, including local schoolchildren. We play a prominent role interacting with schoolchildren by accepting pupils on work experience placements and participating in university open days, science fairs and school visits. This will hopefully allow us to inspire a future generation of biomedical scientists by highlighting the importance of both fundamental research and research into the causes of neurodevelopmental impairments and their treatment. Another societal impact of the research will be the high-quality training that the post-doctoral research assistant will receive, enhancing the skills base of the UK and our global competitiveness.