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Parkinson's Disease and Related Disorders

開催日 2014/9/12
時間 14:00 - 15:00
会場 Poster / Exhibition(Event Hall B)

Protection of differentiated SH-SY5Y cells from MPP+-mediated toxicity by histone deacetylase inhibition

  • P2-298
  • Chi-Jing Choong:1 Toru Yasuda:1 Kousuke Baba:1 Tsutomu Sasaki:1 Shinichi Uesato:2 Hideki Mochizuki:1 
  • 1:Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan 2:Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Osaka, Japan 

Histone deacetylase (HDAC) inhibitors have been proven to be efficacious in neurodegenerative disease. Yet it remains obscure how histone acetylation is transferred to neuroprotection. In this study, we investigated the mechanism underlying neuroprotection conferred by an isoform-specific HDAC inhibitor, compound X, in in vitro Parkinson's Disease (PD) model.
We treated retinoic acid-differentiated human neuroblastoma SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), a mitochondrial complex I inhibitor and examined the effect of compound X co-treatment.
Cotreatment with compound X attenuated MPP+-induced cytotoxicity, as validated by lactate dehydrogenase assay and immunostaining for active caspase 3. Apoptotic array further provided us insights into the mechanisms that led to protective effect of compound X. Compound X treated cells were found to maintain high level of X-linked inhibitor of apoptosis (XIAP) and livin after MPP+ addition, thereby decreased cell death. Downregulation of p53 upregulated modulator of apoptosis (PUMA) and p53 and reduced p53 phosphorylation upon compound X treatment were also observed. Furthermore, the protective effect of compound X was revealed to be mediated by inactivation of SAPK/JNK and Raf-MEK-ERK mitogen-activated protein kinase cascades.
In brief, inhibition of HDACs by compound X reduces the deacetylation of histones which is thought to lead to chromatin relaxation and activation of multiple gene products conducive to neuroprotection.

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