title: Parkin Overexpression Ameliorates PrP106-126-Induced Neurotoxicity via Enhanced Autophagy in N2a Cells.
abstract: Transmissible spongiform encephalopathies (TSEs) are caused by the accumulation of the abnormal prion protein scrapie (PrPSc). Prion protein aggregation, misfolding, and cytotoxicity in the brain are the major causes of neuronal dysfunction and ultimate neurodegeneration in all TSEs. Parkin, an E3 ubiquitin ligase, has been studied extensively in all major protein misfolding aggregating diseases, especially Parkinson's disease and Alzheimer's disease, but the role of parkin in TSEs remains unknown. Here we investigated the role of parkin in a prion disease cell model in which neuroblastoma2a (N2a) cells were treated with prion peptide PrP106-126. We observed a gradual decrease in the soluble parkin level upon treatment with PrP106-126 in a time-dependent manner. Furthermore, endogenous parkin colocalized with FITC-tagged prion fragment106-126. Overexpression of parkin in N2a cells via transfection repressed apoptosis by enhancing autophagy. Parkin-overexpressing cells also showed reductions in apoptotic BAX translocation to the mitochondria and cytochrome c release to the cytosol, which ultimately inhibited activation of proapoptotic caspases. Taken together, our findings reveal a parkin-mediated cytoprotective mechanism against PrP106-126 toxicity, which is a novel potential therapeutic target for treating prion diseases.
authors.affiliation: National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Sher Hayat
authors.initials: SH
authors.lastname: Khan
authors.affiliation: National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Deming
authors.initials: D
authors.lastname: Zhao
authors.affiliation: National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Syed Zahid Ali
authors.initials: SZ
authors.lastname: Shah
authors.affiliation: National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Mohammad Farooque
authors.initials: MF
authors.lastname: Hassan
authors.affiliation: Fujian Agriculture and Forestry University, Fuzhou, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhu
authors.affiliation: National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Song
authors.affiliation: National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: National Animal Transmissible Spongiform Encephalopathy Laboratory, Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China. yanglf@cau.edu.cn.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011328:Prions / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D011328:Prions; D011994:Recombinant Proteins; D045304:Cytochromes c; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020169:Caspases
keywords: Apoptosis; Autophagy; Cytotoxicity; Parkin; PrP106–126; Prion diseases