Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington’s Disease Cells

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1570-1593
Number of pages24
JournalMolecular Neurobiology
Volume57
Issue number3
DOIs
StatePublished - Mar 1 2020

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Keywords

  • Huntington’s Disease Cells
  • Insulin/IGF Receptors
  • Manganese

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Bryan, M. R., Nordham, K. D., Rose, D. I. R., O’Brien, M. T., Joshi, P., Foshage, A. M., Gonçalves, F. M., Nitin, R., Uhouse, M. A., Aschner, M., & Bowman, A. B. (2020). Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington’s Disease Cells. Molecular Neurobiology, 57(3), 1570-1593. https://doi.org/10.1007/s12035-019-01824-1