title: Histone decacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection against MPP+.
abstract: BACKGROUND
  Parkinson's disease (PD) is a common neurodegenerative disease, characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. Recent investigations have shown that mitochondrial fragmentation, an early event during apoptosis, is implicated in the degeneration of DA neurons in PD, and more importantly, preventing mitochondrial fragmentation could rescue cell death in several PD models. Therefore, mitochondrial dynamics may be a therapeutic target for early intervention in PD. However, much remains unknown about the mechanism underlying mitochondrial fragmentation in PD.
  
  
  METHODS
  The alterations in mitochondrial morphology, cell apoptosis, and mitochondrial shaping protein levels were detected after SH-SY5Y cells were treated with various doses of MPP+ or rotenone.
  
  
  RESULTS
  Mitochondrial fragmentation is an early event during apoptosis caused by MPP+ but not rotenone, and Trichostatin A (TSA), a commonly used histone deacetylase (HDAC) inhibitor, selectively rescues mitochondrial fragmentation and cell death induced by lower doses of MPP+. Mitochondrial fragmentation triggered by lower doses of MPP+ may be a result of Mfn2 down-regulation, which could be completely reversed by TSA. Further investigation suggests that TSA prevents MPP+-induced Mfn2 down-regulation via inhibiting histone deacetylation over Mfn2 promoter and alleviating its transcriptional dysfunction.
  
  
  CONCLUSIONS
  Histone deacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection in PD cell model induced by MPP+. Hence, HDAC inhibitors may be a potential early treatment for PD.
authors.affiliation: Laboratory of Neurology of Integrative Medical Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Neurology, Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China; The State Key Laboratory of Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: Chuan-Zhen
authors.initials: CZ
authors.lastname: Lu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000188:drug therapy*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000633:toxicity; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D014475:Uncoupling Agents; D051028:bcl-2-Associated X Protein; D012402:Rotenone; C012589:trichostatin A; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human; D015655:1-Methyl-4-phenylpyridinium
keywords: Early neuroprotection; Histone deacetylase inhibitors; Mitochondrial fragmentation; Parkinson's disease