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UBC Theses and Dissertations

Regulation of dendritic morphology and synapse formation by the intellectual disability associated palmitoyl acyl transferases zDHHC15 and zDHHC9 Shimell, Jordan J.

Abstract

Palmitoylation is a reversible post-translational modification that facilitates vesicular transport and subcellular localization of modified proteins. This process is catalyzed by a family of palmitoyl acyltransferases known as zDHHC enzymes and mounting evidence suggests that these enzymes play key roles in the development and function of neuronal connections. Additionally, a number of zDHHCs have been associated with neurodevelopmental, neurological and neurodegenerative diseases. Loss-of-function variants in zDHHC15 and zDHHC9 are associated with intellectual disabilities; however, there is limited information on the function of these enzymes in the brain. This dissertation discusses work that demonstrates that zDHHC15 and zDHHC9 palmitoylation independently regulate dendritic arborization and are required for the formation and/or maintenance of excitatory (zDHHC15) and inhibitory (zDHHC9) synapses, thereby regulating the balance between excitation and inhibition. Loss of zDHHC15 function inhibits dendrite growth and decreases the palmitoylation and trafficking of PSD-95 into dendrites, leading to deficits in spine maturation. Loss of zDHHC9 function promotes dendritic retraction through aberrant palmitoylation of the small GTPase, Ras, and decreases the formation/maintenance of inhibitory synapses by decreasing the palmitoylation of the small GTPase, TC10. As well, knocking out zDHHC9 in mice results in decreased palmitoylation of Ras and TC10, and leads to elevated synaptic excitability and seizure-like activity. This work provides new insights into the function of zDHHC15 and zDHHC9 and provides a plausible mechanism for how loss-of-function mutations in these proteins may contribute to the etiology of intellectual disability

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