Cell-penetrating, antioxidant SELENOT mimetic protects dopaminergic neurons and ameliorates motor dysfunction in Parkinson’s disease animal models
Redox Biology. 2021-04-01; 40: 101839
DOI: 10.1016/j.redox.2020.101839
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Alsharif I(1), Boukhzar L(2), Lefranc B(3), Godefroy D(2), Aury-Landas J(4),
Rego JD(5), Rego JD(5), Naudet F(6), Arabo A(7), Chagraoui A(2), Maltête D(2),
Benazzouz A(6), Baugé C(4), Leprince J(3), Elkahloun AG(8), Eiden LE(9), Anouar
Y(10).
Author information:
(1)UNIROUEN, Inserm U1239, Neuronal and Neuroendocrine Differentiation and
Communication Laboratory, Rouen Normandie University, 76821, Mont-Saint-Aignan,
France; Institute for Research and Innovation in Biomedicine, 76000, Rouen,
France; Biology department, Jamoum University College, Umm Alqura University,
Saudi Arabia.
(2)UNIROUEN, Inserm U1239, Neuronal and Neuroendocrine Differentiation and
Communication Laboratory, Rouen Normandie University, 76821, Mont-Saint-Aignan,
France; Institute for Research and Innovation in Biomedicine, 76000, Rouen,
France.
(3)UNIROUEN, Inserm U1239, Neuronal and Neuroendocrine Differentiation and
Communication Laboratory, Rouen Normandie University, 76821, Mont-Saint-Aignan,
France; Institute for Research and Innovation in Biomedicine, 76000, Rouen,
France; PRIMACEN, Cell Imaging Platform of Normandie, UNIROUEN, 76000, Rouen,
France.
(4)UNICAEN, BioConnecT EA7451, 14000, Caen, France.
(5)Institute for Research and Innovation in Biomedicine, 76000, Rouen, France;
Behavioral Analysis Platform SCAC, Rouen Medical School, Rouen Normandie
University, 76183, Rouen, France.
(6)Institut des Maladies Neurodégénératives, CNRS, UMR 5293, Bordeaux
University, F-33000, Bordeaux, France.
(7)Biological Resource Service (SRB), Faculty of Sciences and Techniques, Rouen
Normandie University, 76821, Mont-Saint-Aignan, France.
(8)Comparative Genomics and Cancer, Genetics Branch, National Human Genome
Research Institute, National Institutes of Health, Bethesda, MD, USA.
(9)Section on Molecular Neuroscience, National Institute of Mental Health
Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
(10)UNIROUEN, Inserm U1239, Neuronal and Neuroendocrine Differentiation and
Communication Laboratory, Rouen Normandie University, 76821, Mont-Saint-Aignan,
France; Institute for Research and Innovation in Biomedicine, 76000, Rouen,
France. Electronic address: .
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.
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.redox.2020.101839
PMCID: PMC7823055
PMID: 33486153 [Indexed for MEDLINE]
Conflict of interest statement: There is no conflict of interest.