Jordan James Shimell, University of British Columbia
Shimell, Jordan J., Shah, Bhavin S., Cain, Stuart M., Thouta, Samrat, Kuhlmann, Naila, Tatarnikov, I., Jovellar, D. Blair, Brigidi, G. Stefano, Kass, Jennifer, Milnerwood, Austen J., Snutch, Terrance, and Bamji, Shernaz X. The X-linked intellectual disability gene Zdhhc9 is essential for dendrite outgrowth and inhibitory synapse formation. Cell Reports, 29, 2422-2437. 2019 Nov 19 Open access https://www.sciencedirect.com/science/article/pii/S2211124719313798
Dr. Jordan James Shimell lives in Richmond, British Columbia.
Understanding X-linked intellectual disability
Intellectual disability is characterized by poor general mental capacity that affects learning, reasoning and problem solving, and is caused by disruptions in the proper development of the brain, and in particular, disruptions in brain connections called ‘synapses’. There is growing evidence that a protein modification known as ‘palmitoylation’, which adds a lipid chain to facilitate targeting, trafficking, and function of proteins, may play an important role at synapses. In fact, nearly 2% of all patients who have intellectual disability linked to the X chromosome have mutations in one of the enzymes that mediates palmitoylation, called ZDHHC9. These patients also have an elevated risk of epilepsy compared to other intellectual disability patients, but despite this the role of ZDHHC9 in shaping neuronal connectivity has not been examined.
Dr. Jordan Shimell, a PhD student in the laboratory of Dr. Shernaz Bamji at the University of British Columbia, studied the role of ZDHHC9 in brain connectivity. His results showed that ZDHHC9 regulates neuron growth, as neurons lacking ZDHHC9 had shorter, less complicated dendrites, which are the branches of neurons that receive inputs from other cells. Additionally, Jordan’s work showed that ZDHHC9 modified the balance of excitatory and inhibitory synapses formed onto these cells, specifically through a mechanism leading to a reduction in inhibitory synapses. These findings further our understanding of the role of palmitoylation in the nervous system and may provide the foundations for therapeutic interventions for patients with alterations in ZDHHC9 function.
Dr. Shimell’s work offers new clarity on the role of ZDHHC9 at the cellular level and its implications for circuit development. “We have demonstrated that loss of ZDHHC9 function can disrupt dendrite outgrowth and shift the ratio of excitatory-to-inhibitory synapses, possibly resulting in seizure disorders such as epilepsy,” Dr. Shimell said. “Our findings offer a plausible mechanism for how loss of ZDHHC9 might contribute to intellectual disability and epilepsy.
Dr. Jordan Shimell
Dr. Jordan Shimell performed this works as a Ph.D. student in the laboratory of Dr. Shernaz Bamji at the University of British Columbia. He is the first author on this study and solely responsible for most of the design, execution and analysis of experiments. This work consisted of the bulk of Dr. Shimell’s PhD thesis. Dr. Shimell wrote the first draft of the manuscript and was actively involved in the editing process along with his supervisor, Dr. Bamji. Dr. Shimell approached this project with tenacity, and when faced with the challenge of determining the mechanism by which ZDHHC9 regulated the formation of inhibitory synapses, identified a target through the voracious study of the literature and the synthesis of several different studies.
This research was supported by the Canadian Institutes of Health Research