Title: Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells.

Authors: Bryan, Miles R; Nordham, Kristen D; Rose, Daniel I R; O'Brien, Michael T; Joshi, Piyush; Foshage, Audra M; Gonçalves, Filipe M; Nitin, Rachana; Uhouse, Michael A; Aschner, Michael; Bowman, Aaron B

Published In Mol Neurobiol, (2020 Mar)

Abstract: Perturbations in insulin/IGF signaling and manganese (Mn2+) uptake and signaling have been separately reported in Huntington's disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn2+-responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn2+ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn2+ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn2+-dependent AKT signaling is predominantly mediated by direct Mn2+ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn2+ bioavailability. We examined the combined effects of IGF-1 and/or Mn2+ treatments on AKT signaling in multiple HD cellular models. Mn2+ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70-80% of Mn2+-associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn2+-induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn2+ and IGF-1. Lastly, Mn2+-induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn2+ supplementation. Our data demonstrate that Mn2+ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn2+ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.

PubMed ID: 31797328

MeSH Terms: Animals; Biological Transport/physiology; Glucose/metabolism; Huntington Disease/genetics; Huntington Disease/metabolism*; Insulin-Like Growth Factor I/metabolism*; Phosphorylation; Proto-Oncogene Proteins c-akt/metabolism*; Rats; Receptor, IGF Type 1/metabolism; Receptor, Insulin/metabolism*; Signal Transduction/physiology