Abstract
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.
Highlights
The Prolyl isomerases (Peptidylprolyl isomerases, PPIases) are a class of enzymes that catalyze the cis/trans isomerization of the peptide bond between the preceding amino acid and the proline (Pro) residue [1,2,3,4]
In an in vitro system of human neuroblastoma cell line, SH-SY5Y, we silenced the expression of Peptidylprolyl cis/trans isomerase NIMA-interacting 1 (Pin1) gene by RNA interference technique
Liraglutide Enhanced Cell Viability in Presence of Impaired Glycolysis First we evaluated the response of knock down (KD) clones to defective/impaired glycolysis
Summary
The Prolyl isomerases (Peptidylprolyl isomerases, PPIases) are a class of enzymes that catalyze the cis/trans isomerization of the peptide bond between the preceding amino acid and the proline (Pro) residue [1,2,3,4]. The PPIases modulate their stability, enzyme activities and subcellular localization by catalyzing conformational changes of their substrates [3,5,6]. The Peptidylprolyl cis/trans isomerase NIMA-interacting 1 (Pin1) belongs to one of the three classes of PPIases. Main distinctive feature of Pin is that its substrates are phosphorylated by proline-directed kinases. Pin requires that the Serine (Ser) or the Threonine (Thr) that precede Pro residue are phosphorylated to ensure catalysis [3,7]. Dysfunctional expression of Pin causes deregulation of Pin substrates, a phenomenon that is associated with the onset of neurodegenerative and metabolic disorders including type 2 diabetes (T2D) [1,3,8,9,10,11,12]
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