1. Cell-penetrating, antioxidant SELENOT mimetic protects dopaminergic neurons and ameliorates motor dysfunction in Parkinson's disease animal models
- Author
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Ifat Alsharif, Loubna Boukhzar, Benjamin Lefranc, David Godefroy, Juliette Aury-Landas, Jean-Luc do Rego, Jean-Claude do Rego, Frédéric Naudet, Arnaud Arabo, Abdeslam Chagraoui, David Maltête, Abdelhamid Benazzouz, Catherine Baugé, Jérôme Leprince, Abdel G. Elkahloun, Lee E. Eiden, Youssef Anouar, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biotechnologie des tissus conjonctifs et cutanés / Biology of Connective and Cutaneous Tissues (BioConnecT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Service Commun d'Analyse Comportementale (SCAC), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU), Comparative Genomics and Cancer, Section on Molecular Neuroscience, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Human Genome Research Institute (NHGRI), Laboratory of Cellular and Molecular Regulation, National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), and CCSD, Accord Elsevier
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lcsh:R5-920 ,Dopaminergic Neurons ,[SDV]Life Sciences [q-bio] ,Parkinson Disease ,Neuron ,Neurodegenerative disease ,Selenoprotein ,Antioxidants ,[SDV] Life Sciences [q-bio] ,Disease Models, Animal ,Neuroprotective Agents ,lcsh:Biology (General) ,Oxidative stress ,Peptide therapy ,Animals ,lcsh:Medicine (General) ,lcsh:QH301-705.5 ,Research Paper - Abstract
International audience; Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction for which there is an unmet need for better treatment options. Although oxidative stress is a common feature of neurodegenerative diseases, notably PD, there is currently no efficient therapeutic strategy able to tackle this multi-target pathophysiological process. Based on our previous observations of the potent antioxidant and neuroprotective activity of SELENOT, a vital thioredoxin-like selenoprotein, we designed the small peptide PSELT from its redox active site to evaluate its antioxidant properties in vivo, and its potential polyfunctional activity in PD models. PSELT protects neurotoxin-treated dopaminergic neurons against oxidative stress and cell death, and their fibers against neurotoxic degeneration. PSELT is cell-permeable and acts in multiple subcellular compartments of dopaminergic neurons that are vulnerable to oxidative stress. In rodent models of PD, this protective activity prevented neurodegeneration, restored phosphorylated tyrosine hydroxylase levels, and led to improved motor skills. Transcriptomic analysis revealed that gene regulation by PSELT after MPP+ treatment negatively correlates with that occurring in PD, and positively correlates with that occurring after resveratrol treatment. Mechanistically, a major impact of PSELT is via nuclear stimulation of the transcription factor EZH2, leading to neuroprotection. Overall, these findings demonstrate the potential of PSELT as a therapeutic candidate for treatment of PD, targeting oxidative stress at multiple intracellular levels.
- Published
- 2021