Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson's Disease

Histone deacetylase 4 (HDAC4) is a class II HDAC which is highly expressed in the brain. Previous reports have shown that HDAC4 is essential for normal brain physiology and its deregulation leads to several neurodegenerative disorders. However, it remains unclear whether dysregulation of HDAC4 is specifically involved in the development of Parkinson's disease. In this study, we demonstrate that intracellular trafficking of HDAC4 is important in regulating dopaminergic cell death. While HDAC4 normally localizes to the cytoplasm, nuclear accumulation of HDAC4 was observed in dopaminergic neurons overexpressing A53T mutant alpha-synuclein treated with MPP+/MPTP in vitro and in vivo. Nuclear-localized HDAC4 repressed cAMP response element-binding protein (CREB) and myocyte enhancer factor 2A (MEF2A), altered neuronal gene expression, and promoted neuronal apoptosis. Furthermore, cytoplasm-to-nucleus shuttling of HDAC4 was determined by its phosphorylation status, which was regulated by PP2A and PKC epsilon. Treatment with PKC epsilon-specific activators, DCP-LA or Bryostatin 1, provided neuroprotection against MPP+ toxicity in a dose-dependent manner. In summary, our research illustrated that intracellular trafficking of HDAC4 contributes to the vulnerability of cells expressing pathogenic alpha-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKC epsilon activators that may serve as therapeutic agents for Parkinson's disease.