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

## TL;DR

This study shows that HDAC4 protein forms nuclear condensates in fruit flies, which disrupts brain development and suggests targeting these structures could help treat related disorders.

## Contribution

The study reveals that HDAC4 nuclear condensation is driven by self-oligomerization and worsened by MEF2, offering new therapeutic strategies for neurodevelopmental diseases.

## Key findings

- HDAC4 nuclear condensation correlates with neurodevelopmental defects in Drosophila mushroom body and eye development.
- Blocking HDAC4 oligomerization reduces condensation and severity of neurodevelopmental phenotypes.
- MEF2 stabilizes HDAC4 condensates and increases phenotypic severity.

## Abstract

Histone deacetylase four (HDAC4) undergoes dynamic nucleocytoplasmic shuttling, a process critical for regulating 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, ultimately exacerbating phenotypic severity. These data provide insight into the role of HDAC4 condensates in normal neuronal function and suggest that their dysregulation may contribute to neurodevelopmental disorders. Consequently, targeting oligomerization of HDAC4 and its interaction with MEF2 present potential therapeutic strategies for diseases associated with HDAC4 nuclear accumulation.