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

Summary

This study reveals how a protein called HDAC4 forms clumps inside cell nuclei, which damages brain development. Researchers found that the protein’s ability to stick to itself (oligomerize) drives this clumping process. By modifying the protein to prevent self-sticking, they reduced the damage to developing brain structures, suggesting new ways to treat brain disorders linked to HDAC4 accumulation.

Background

Histone deacetylase four (HDAC4) undergoes dynamic nucleocytoplasmic shuttling critical for regulating its activity. Aberrant nuclear accumulation of HDAC4 is associated with neurodevelopmental and neurodegenerative diseases, and in Drosophila models, impairs normal neuronal development through formation of biomolecular condensates.

Objective

To determine whether HDAC4 oligomerization is required for nuclear condensate formation and whether disrupting oligomerization reduces condensation and severity of neurodevelopmental phenotypes in Drosophila. The study also aimed to characterize the role of MEF2 in stabilizing HDAC4 condensates.

Results

HDAC4 oligomerization via N-terminal α-helix is essential for nuclear condensate formation and correlates with severity of neurodevelopmental defects in mushroom body and eye development. MEF2 binding promotes condensate formation and stabilization. Impairing oligomerization reduced condensate formation and phenotypic severity, while enhancing oligomerization exacerbated defects.

Conclusion

HDAC4 condensation is mediated by self-oligomerization and stabilized by MEF2, contributing to neurodevelopmental dysfunction. Targeting HDAC4 oligomerization and MEF2 interaction present potential therapeutic strategies for diseases associated with nuclear HDAC4 accumulation, including neurodevelopmental disorders and Alzheimer’s disease.
  • Published in:Open Biology,
  • Study Type:Research Article - Experimental Study,
  • Source: PMID: 41151763
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