Investigating the role of HDAC4 subcellular distribution in Drosophila development and memory : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy (PhD) in Biochemistry at Massey University, Manawatū, New Zealand. EMBARGOED until 16 May 2021.

Abstract

The class IIa histone deacetylase HDAC4 has been previously demonstrated to play an essential role in brain development, learning and memory. However, the molecular pathways through which it acts are unknown. HDAC4 undergoes activity-dependent nucleocytoplasmic shuttling, and disruption of the balance of nuclear and cytoplasmic HDAC4 has been identified as a factor in developmental and neurodegenerative disorders. This project used Drosophila melanogaster as a model to investigate the effects of altered subcellular distribution of HDAC4 on neural development and memory formation through the overexpression of Drosophila HDAC4 and wild-type human HDAC4 (hHDAC4), as well as nuclear- and cytoplasm-localising mutants of hHDAC4 named 3SA and L175A, respectively. This project has shown that nuclear but not cytoplasmic HDAC4 impairs development and memory in Drosophila. Furthermore, cytoplasmic HDAC4 may play a role in transcriptional regulation of neurons, possibly regulation metabolic activity, suggesting that the activity-dependent nucleocytoplasmic shuttling of HDAC4 may not be primarily to remove HDAC4 from the nucleus but instead to return HDAC4 to the cytoplasm.--Shortened abstract