Oral Presentation 16th Asian Conference on Transcription 2019

Investigating nuclear and cytoplasmic roles of HDAC4 in the brain (1094)

Helen L Fitzsimons 1 , Patrick J Main 1
  1. School of Fundamental Sciences, Massey University, Palmerston North, MANAWATU, New Zealand

Both neuronal development and memory formation involve epigenetic mechanisms that coordinate changes in gene expression that lead to synaptic rearrangement and growth. Haploinsufficiency of the histone deacetylase HDAC4 is associated with intellectual disability and developmental delay in humans, indicating that it plays an essential role in normal neuronal function. However HDAC4 is increased in abundance in brains of individuals with Alzheimer’s disease and we have shown in our Drosophila model that overexpression results in severe developmental malformation of the brain and also prevents long-term memory formation in the adult fly. Unlike most other HDACs, HDAC4 undergoes nucleocytoplasmic shuttling and is largely non-nuclear in neurons, therefore to investigate whether these phenotypes were due to increased abundance of nuclear and/or cytoplasmic HDAC4, we expressed HDAC4 mutants that were restricted to either the nucleus (3SA) or cytoplasm (L175A) of neurons and examined the impact on development and long-term memory. Severe developmental defects and memory deficits were observed on expression of 3SA whereas L175A had no impact. RNA-seq surprisingly revealed that expression of only 29 genes was significantly altered by 3SA, suggesting that HDAC4 may be acting through largely non-transcriptional mechanisms. HDAC4 aggregates into punctate foci in nuclei through tetramerisation of its glutamine-rich N-terminus. An increasing number of studies have identified HDAC4 to be present in intranuclear and cytoplasmic inclusion associated with several neurodegenerative disorders, therefore further investigation is warranted into whether the impairments in neuronal function are caused by intranuclear aggregation of HDAC4.