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Open AccessArticle

Liraglutide Treatment Ameliorates Neurotoxicity Induced by Stable Silencing of Pin1

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Research Area for Multi-factorial Diseases, Obesity and Diabetes, Bambino Gesù Children’s Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy
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Confocal Microscopy Core Facility, Research Laboratories, Bambino Gesu’ Children’s Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy
3
Molecular Genetics of Complex Phenotypes Research Unit, Bambino Gesù Children’s Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(20), 5064; https://doi.org/10.3390/ijms20205064
Received: 30 September 2019 / Accepted: 11 October 2019 / Published: 12 October 2019
Post-translational modulation of peptidylprolyl isomerase Pin1 might link impaired glucose metabolism and neurodegeneration, being Pin1 effectors target for the glucagon-Like-Peptide1 analog liraglutide. We tested the hypotheses in Pin1 silenced cells (SH-SY5Y) treated with 2-deoxy-d-glucose (2DG) and methylglyoxal (MG), stressors causing altered glucose trafficking, glucotoxicity and protein glycation. Rescue by liraglutide was investigated. Pin1 silencing caused increased levels of reactive oxygen species, upregulated energy metabolism as suggested by raised levels of total ATP content and mRNA of SIRT1, PGC1α, NRF1; enhanced mitochondrial fission events as supported by raised protein expression of FIS1 and DRP1. 2DG and MG reduced significantly cell viability in all the cell lines. In Pin1 KD clones, 2DG exacerbated altered mitochondrial dynamics causing higher rate of fission events. Liraglutide influenced insulin signaling pathway (GSK3b/Akt); improved cell viability also in cells treated with 2DG; but it did not revert mitochondrial dysfunction in Pin1 KD model. In cells treated with MG, liraglutide enhanced cell viability, reduced ROS levels and cell death (AnnexinV/PI); and trended to reduce anti-apoptotic signals (BAX, BCL2, CASP3). Pin1 silencing mimics neuronal metabolic impairment of patients with impaired glucose metabolism and neurodegeneration. Liraglutide rescues to some extent cellular dysfunctions induced by Pin1 silencing. View Full-Text
Keywords: Alzheimer’s disease; brain insulin resistance; brain glucotoxicity; Pin1; type 2 diabetes; type 3 diabetes; 2-deoxy-d-glucose; methylglyoxal; liraglutide Alzheimer’s disease; brain insulin resistance; brain glucotoxicity; Pin1; type 2 diabetes; type 3 diabetes; 2-deoxy-d-glucose; methylglyoxal; liraglutide
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Bianchi, M.; D’Oria, V.; Braghini, M.R.; Petrini, S.; Manco, M. Liraglutide Treatment Ameliorates Neurotoxicity Induced by Stable Silencing of Pin1. Int. J. Mol. Sci. 2019, 20, 5064.

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  • Supplementary File 1:

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    Doi: 10.5281/zenodo.3465644
    Description: Supplementary Figure S1. A. Cell viability of SH-SY5Y cells exposed at different concentrations of Lira (0, 50, 100, 200 nM) for 5h. B. Evaluation of cell toxicity of SH-SY5Y cells to 2DG treatment. Cells were starved in serum free medium for 5h then SH-SY5Y cells were exposed to different concentrations of 2DG (0, 25, 50, 100 mM) for 1h. C. Evaluation of cell toxicity of SH-SY5Y cells to MG treatment. Cells were starved in serum free medium for 5h then SH-SY5Y cells were exposed to different concentrations of MG (0, 300, 600 M) in serum free medium for 24h .
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