N-terminal oligomerization drives HDAC4 nuclear condensation and neurodevelopmental dysfunction in Drosophila

Abstract Histone deacetylase four (HDAC4) undergoes dynamic nucleocytoplasmic shuttling, which is important in the regulation of its activity. However, aberrant nuclear accumulation of HDAC4 is associated with both neurodevelopmental and neurodegenerative disease, and in our Drosophila model, impairs normal neuronal development. Upon nuclear accumulation, HDAC4 forms biomolecular condensates, previously termed aggregates, that correlate with the severity of defects in development of the Drosophila mushroom body and adult eye. Here we determined that nuclear condensation of HDAC4 is dependent on self-oligomerization, and that impairing oligomerization reduces condensation and the severity of neurodevelopmental phenotypes in Drosophila. HDAC4 condensates are highly dynamic and are stabilized by the presence of MEF2, which promotes their formation and coalescence, ultimately exacerbating phenotypic severity. These data provide insight into the role of HDAC4 condensates in normal neuronal function and suggest that their disruption may contribute to the onset or progression of neuronal disease. Consequently, targeting oligomerization of HDAC4 and its interaction with MEF2 present potential therapeutic strategies for diseases associated with HDAC4 nuclear accumulation. Competing Interest Statement The authors have declared no competing interest.