Tau Protein as a New Regulator of Cellular Prion Protein Transcription
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Tau Protein as a New Regulator of Cellular Prion Protein Transcription Laia Lidón 1,2,3,4 & Cristina Vergara 5 & Isidro Ferrer 3,4,6,7 & Félix Hernández 3,8 & Jesús Ávila 3,8 & Jose A. del Rio 1,2,3,4 Rosalina Gavín 1,2,3,4
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Received: 19 March 2020 / Accepted: 14 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Cellular prion protein (PrPC) is largely responsible for transmissible spongiform encephalopathies (TSEs) when it becomes the abnormally processed and protease resistant form PrPSC. Physiological functions of PrPC include protective roles against oxidative stress and excitotoxicity. Relevantly, PrPC downregulates tau levels, whose accumulation and modification are a hallmark in the advance of Alzheimer’s disease (AD). In addition to the accumulation of misfolded proteins, in the initial stages of AD-affected brains display both increased reactive oxygen species (ROS) markers and levels of PrPC. However, the factors responsible for the upregulation of PrPC are unknown. Thus, the aim of this study was to uncover the different molecular actors promoting PrPC overexpression. In order to mimic early stages of AD, we used β-amyloid-derived diffusible ligands (ADDLs) and tau cellular treatments, as well as ROS generation, to elucidate their particular roles in human PRNP promoter activity. In addition, we used specific chemical inhibitors and site-specific mutations of the PRNP promoter sequence to analyze the contribution of the main transcription factors involved in PRNP transcription under the analyzed conditions. Our results revealed that tau is a new modulator of PrPC expression independently of ADDL treatment and ROS levels. Lastly, we discovered that the JNK/c-jun-AP-1 pathway is involved in increased PRNP transcription activity by tau but not in the promoter response to ROS. Keywords Cellular prion protein . Tau . Promoter . Alzheimer’s disease . Tauopathies
Introduction During the progression of prionopathies, the abnormal processing of cellular prion protein (PrPC) gives rise to a protease-resistant form of the protein, PrPSC [1, 2], responsible for the transmissible spongiform encephalopathies (TSEs) that
include Creutzfeldt-Jacob disease (CJD), GerstmannSträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI) in humans. Thus, TSE clinical phenotypes should be considered as additional effects of the loss of function of natural PrPC together with the neurotoxic effects of pathogenic prions [3].
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02025-x) contains supplementary material, which is available to authorized users. * Jose A. del Rio [email protected] * Rosalina Gavín [email protected] 1
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Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Scientific Park of Barcelona, The Barcelona Institute for Science and Technology (BIST), Baldiri and Reixac 15-21, 08028 Barcelona, Spain Department of Cell Biology, Physiology and Immunology, Faculty
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