Focus on the foci: Investigating the role of HDAC4 aggregation in neuronal development in Drosophila melanogaster
Authors: Hannah Hawley; Helen Fitzsimons
Affiliation: School of Natural Sciences, Massey University, New Zealand
Keywords: k. developmental disorders; j. epigenetics
Dysregulation of histone deacetylase 4 (HDAC4) expression and subcellular distribution has been observed in a number of neurodevelopmental and neurodegenerative diseases, and in our Drosophila melanogaster model, HDAC4 overexpression impairs neuronal development and long-term memory. Interestingly, this is associated with minimal transcriptional changes. Upon increased abundance in nuclei, we observe HDAC4 aggregation into punctate foci, and therefore hypothesise that neuronal dysfunction mediated by HDAC4 overexpression is a result of aggregate formation.
The glutamine-rich N-terminus of HDAC4 forms an alpha helix which assembles into an unstable tetramer. To investigate whether HDAC4 aggregates contribute to neurodevelopmental deficits, transgenic Drosophila were generated which express HDAC4 mutants harbouring structure-guided substitutions of key amino acids important in mediating tetramerization. Expression of these mutant HDAC4 constructs significantly reduced aggregate formation in neuronal nuclei (ANOVA, p < 0.01), and this correlated with a significant reduction in defects in axon morphogenesis (Fisher’s exact, p < 0.01) and photoreceptor development (ANOVA, p < 0.01), as compared to wild-type HDAC4. These data suggest HDAC4 aggregation is at least in part responsible for neurodevelopmental and neurodegenerative disease in which HDAC4 is aberrantly expressed, and warrants further studies into the composition of these aggregates as well as strategies to mitigate their formation.