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Parkin Overexpression Ameliorates PrP106–126-Induced Neurotoxicity via Enhanced Autophagy in N2a Cells

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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.

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Acknowledgments

This work was supported by the Natural Science Foundation of China (No. 31272532) and the Foundation of Chinese Ministry of Science and Technology (Project No. 2015BAI07B02).

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    1. 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

      Sher Hayat Khan, Deming Zhao, Syed Zahid Ali Shah, Mohammad Farooque Hassan, Zhiqi Song, Xiangmei Zhou & Lifeng Yang

    2. Fujian Agriculture and Forestry University, Fuzhou, China

      Ting Zhu

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    S. H. Khan and D. Zhao equally contributed to this work.

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    Khan, S.H., Zhao, D., Shah, S.Z.A. et al. Parkin Overexpression Ameliorates PrP106–126-Induced Neurotoxicity via Enhanced Autophagy in N2a Cells. Cell Mol Neurobiol 37, 717–728 (2017). https://doi.org/10.1007/s10571-016-0407-7

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