Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?

Abstract

Prolyl isomerases (Peptidylprolyl isomerase, PPIases) are enzymes that catalyze the isomerization between the cis/trans Pro conformations. Three subclasses belong to the class: FKBP (FK506 binding protein family), Cyclophilin and Parvulin family (Pin1 and Par14). Among Prolyl isomerases, Pin1 presents as distinctive feature, the ability of binding to the motif pSer/pThr-Pro that is phosphorylated by kinases. Modulation of Pin1 is implicated in cellular processes such as mitosis, differentiation and metabolism: The enzyme is dysregulated in many diverse pathological conditions, i.e., cancer progression, neurodegenerative (i.e., Alzheimer’s diseases, AD) and metabolic disorders (i.e., type 2 diabetes, T2D). Indeed, Pin1 KO mice develop a complex phenotype of premature aging, cognitive impairment in elderly mice and neuronal degeneration resembling that of the AD in humans. In addition, since the molecule modulates glucose homeostasis in the brain and peripherally, Pin1 KO mice are resistant to diet-induced obesity, insulin resistance, peripheral glucose intolerance and diabetic vascular dysfunction. In this review, we revise first critically the role of Pin1 in neuronal development and differentiation and then focus on the in vivo studies that demonstrate its pivotal role in neurodegenerative processes and glucose homeostasis. We discuss evidence that enables us to speculate about the role of Pin1 as molecular link in the pathogenesis of type 3 diabetes i.e., the clinical association of dementia/AD and T2D.

Liraglutide Treatment Ameliorates Neurotoxicity Induced by Stable Silencing of Pin1

“…In our study, the GLP-1 analog at a dose of 100 nM compensated neurotoxicity induced by stable silencing of Pin1 on the PI3K/Akt transduction pathway. Along this pathway, Pin1 binds and/or modulates important kinases [1,21]. Liraglutide promoted cytoprotection against 2DG and MG by improving cell viability, reduced redox imbalance and MG induced apoptosis in cells affected by persistent mitochondrial dysfunction [32,37].…”

“…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].…”

“…Pin1 modulates key proteins involved in cellular processes such as mitosis, neuronal differentiation and metabolism. Dysfunctional expression of Pin1 causes deregulation of Pin1 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].…”

“…In the brain, excessive activation of GSK3β promotes abnormal hyper phosphorylation of tau protein, aggravates degeneration of neurons, interferes with normal synaptic plasticity, and accelerates AD pathology process in AD patients [22]. Anomalous regulation of GSK3β activity has been associated to neurodegenerative disorders like AD, and diabetes [1,20,22]. Human Pin1 KD (knock down) cells show reduced level of the GSK3β inactive form (phosphorylated GSK3β pGSK3β) [20].…”

Roles of peptidyl-prolyl isomerase Pin1 in disease pathogenesis

“…However, Pin1 interacts with or regulates other key molecules involved in metabolic diseases, including obesity-related factors AMPK 62 - 65 , PPARγ 66 , and PRDM16 67 ; osteoporosis-related factors Runx2 68 - 70 and BMP2 71 ; and Nash-related factors Smad2/Smad3 and the TGF-β1 pathway 72 . The detailed mechanisms by which Pin1 regulates metabolic diseases are summarized in other reviews 73 , 74 .…”