title: Impairment of proteasome and anti-oxidative pathways in the induced pluripotent stem cell model for sporadic Parkinson's disease.
abstract: BACKGROUND
  Parkinson's disease (PD) is associated with the progressive degeneration of dopaminergic neurons with abnormal accumulation of α-synuclein mainly in the ventral midbrain. However, the lack of live human neurons from PD patients and their heterogeneous pathogenic nature limit mechanistic studies and therefore the development of drugs to modify the disease progression of PD. The evolution of induced pluripotent stem cell (iPSC) technology makes it possible to generate patient-specific neurons to explore the pathogenesis in individual PD patients.
  
  
  METHODS
  We generated PD-iPSCs from a sporadic early onset PD patient carrying a heterozygous deletion of exon 5 (Ex5del) in PARK2. The expression of α-synuclein and proteasome and anti-oxidative functions were examined in differentiated iPSC-derived neurons.
  
  
  RESULTS
  The neurons derived from our PD-iPSCs demonstrated abnormal α-synuclein accumulation and down-regulation of the proteasome and anti-oxidative pathways. Environmental triggers such as proteasome inhibitor MG132 and H2O2 markedly induced cell death, while the proteasome enhancer benzamil and anti-oxidative compound genipin significantly rescued these increased susceptibilities.
  
  
  CONCLUSIONS
  These results demonstrate that unique genetic-environmental interactions are involved in neuronal death in PD patients. Our findings also provide a new model to identify potential disease-modifying strategies and an insight into personalized medicine for patients with PD.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: gophy5128@cgmh.org.tw.
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yi-Jing
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Lin
authors.affiliation: Neuroscience and Mental Health Research Institute, School of Biosciences, Cardiff University, UK.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: I-Cheng
authors.initials: IC
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yen-Shi
authors.initials: YS
authors.lastname: Lo
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsiu-Chuan
authors.initials: HC
authors.lastname: Wu
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: cmchen@cgmh.org.tw.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D007621:Karyotyping; D000071317:Nanog Homeobox Protein / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010300:Parkinson Disease / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D014446:Tyrosine 3-Monooxygenase; D046988:Proteasome Endopeptidase Complex
keywords: Induced pluripotent stem cells; Oxidative stress; Parkinson's disease; Proteasome