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MEK1 transduces the prion protein N2 fragment antioxidant effects

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Abstract

The prion protein (PrPC) when mis-folded is causally linked with a group of fatal neurodegenerative diseases called transmissible spongiform encephalopathies or prion diseases. PrPC normal function is still incompletely defined with such investigations complicated by PrPC post-translational modifications, such as internal cleavage, which feasibly could change, activate, or deactivate the function of this protein. Oxidative stress induces β-cleavage and the N-terminal product of this cleavage event, N2, demonstrates a cellular protective response against oxidative stress. The mechanisms by which N2 mediates cellular antioxidant protection were investigated within an in vitro cell model. N2 protection was regulated by copper binding to the octarepeat domain, directing the route of internalisation, which stimulated MEK1 signalling. Precise membrane interactions of N2, determined by copper saturation, and involving both the copper-co-ordinating octarepeat region and the structure conferred upon the N-terminal polybasic region by the proline motif, were essential for the correct engagement of this pathway. The phenomenon of PrPC post-translational modification, such as cleavage and copper co-ordination, as a molecular “switch” for activation or deactivation of certain functions provides new insight into the apparent multi-functionality of PrPC.

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Acknowledgments

The authors would like to thank Dr Victoria Lawson for her support and helpful discussions. The CF10 cells were a kind gift to Dr Victoria Lawson from Dr Suzette Priola (National Institute of Health, USA). This work was supported by an NH&MRC program grant (#628946) and SJC is supported by an NH&MRC Practitioner Fellowship (#APP100581).

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Authors and Affiliations

  1. Department of Pathology, Melbourne Brain Centre, The University of Melbourne, Parkville, Melbourne, 3010, Australia

    C. L. Haigh, A. R. McGlade & S. J. Collins

  2. Mental Health Research Institute, The University of Melbourne, Parkville, Melbourne, 3010, Australia

    A. R. McGlade

  3. Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia

    S. J. Collins

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Haigh, C.L., McGlade, A.R. & Collins, S.J. MEK1 transduces the prion protein N2 fragment antioxidant effects. Cell. Mol. Life Sci. 72, 1613–1629 (2015). https://doi.org/10.1007/s00018-014-1777-y

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