The X-Linked Intellectual Disability Gene Zdhhc9 Is Essential for Dendrite Outgrowth and Inhibitory Synapse Formation
This week we profile a recent publication in Cell Reports from Dr. Jordan Shimell (pictured, left) in the laboratory
of Dr. Shernaz Bamji (pictured, second from left) at the Djavad Mowafaghian Centre for Brain Health.
Can you provide a brief overview of your lab’s current research focus?
Our work demonstrates that DHHC enzymes, which mediate the posttranslational palmitoylation of proteins, are master regulatory ‘hubs’ for activity-dependent structural and functional plasticity critical to proper circuit formation (Nat Neurosci, 2014; Nat Commun, 2015). Building on these findings, we are currently exploring the roles of these enzymes in regulating synapse formation and plasticity, cognition and behavior. This is exceedingly important as 9 of the 23 DHHC enzymes have been linked to neurological disorders thus far and ~41% of all synaptic proteins are substrates for palmitoylation. We are one of a few labs worldwide studying this fundamental process in the brain.
What is the significance of the findings in this publication?
Loss-of-function variants in ZDHHC9 have been identified in patients with X-linked intellectual disability (XLID) (Raymond et al., 2007; Masurel-Paulet et al., 2014; Mitchell et al., 2014; Baker et al., 2015; Tzschach et al., 2015; Han et al., 2017), with ~2% of XLID patients exhibiting mutations in ZDHHC9 (Raymond et al., 2007; Tzschach et al., 2015). Patients with XLID plus ZDHHC9 mutations also have an elevated incidence of epilepsy compared to XLID patients with intact ZDHHC9 (Baker et al., 2015). We demonstrate that loss of Zdhhc9 can increase the ratio of excitatory-to-inhibitory (E:I) synapses and disrupt proper dendritic arborization, presenting a plausible mechanism for how loss of ZDHHC9 function may contribute to XLID and epilepsy.
What are the next steps for this research?
Zdhhc9 expression is extremely highly expressed in myelinating oligodendrocytes. we are really interested in understanding the role of this enzyme in regulating oligodendrocyte development, as well as regulating myelination of neurons.
This work was funded by:
This work was funded by the CIHR.