Our research programme is focused on understanding the molecular processes that are required for formation and storage of memory, and how their disruption can lead to neurological disease. In recent years it has become clear that abnormal accumulation of the histone deacetylase HDAC4 in neuronal nuclei is associated with both neurodevelopmental and neurodegenerative disorders, and in our *Drosophila* model, increased nuclear HDAC4 also impairs neuronal development and memory. When increased in abundance in nuclei, HDAC4 forms into aggregates, which is mediated through an N-terminal *a*-helix. We have determined that mutation of amino acids predicted to prevent tetramerisation both prevents aggregate formation and reverses any developmental deficits. These preliminary data strongly suggest that the aggregates are responsible for the impairments, but it is not clear what causes these aggregates to form, their composition and what it is that makes them pathogenic.
This project seeks to answer these questions. Approaches include determining the impact of specific mutations on the formation of the N-terminal *a*-helix and tetramer of recombinant HDAC4 protein via a variety of biochemical techniques under the guidance of co-supervisor Assoc Prof Andrew Sutherland-Smith. It will also include testing strategies to ameliorate aggregation-induced impairments in *Drosophila* models of neurodegeneration.