title: Nuclear Accumulation of Histone Deacetylase 4 (HDAC4) Exerts Neurotoxicity in Models of Parkinson's Disease.
abstract: 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 α-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 PKCε. Treatment with PKCε-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 α-synuclein mutants in response to oxidative stress and compounds which maintain cytoplasmic localization of HDAC4 such as PKCε activators that may serve as therapeutic agents for Parkinson's disease.
authors: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China.
authors: Qimei
authors: Q
authors: Wu
authors: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China.
authors: Xiaoyu
authors: X
authors: Yang
authors: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China.
authors: Lei
authors: L
authors: Zhang
authors: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China.
authors: Yu
authors: Y
authors: Zhang
authors: CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zu Chong Zhi Road, Shanghai, 201203, People's Republic of China. lyfeng@simm.ac.cn.
authors: Linyin
authors: L
authors: Feng
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009498:Neurotoxins / Q000378:metabolism*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D009498:Neurotoxins; D047428:Protein Kinase Inhibitors; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051744:Protein Kinase C-epsilon; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: HDAC4; Neuroprotection; PKC; Parkinson’s disease; α-Synuclein