A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease

Andrew M. Tidball, Miles R. Bryan, Michael A. Uhouse, Kevin K. Kumar, Asad A. Aboud, Jack E. Feist, Kevin C. Ess, M. Diana Neely, Michael Aschner, Aaron B. Bowman

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The essential micronutrient manganese is enriched in brain, especially in the basal ganglia.We sought to identify neuronal signaling pathways responsive to neurologically relevantmanganese levels, as previous data suggested that alterations in striatal manganese handling occur in Huntington's disease (HD) models.We found that p53 phosphorylation at serine 15 is the most responsive cell signaling event to manganese exposure (of 18 tested) in human neuroprogenitors and a mouse striatal cell line. Manganese-dependent activation of p53 was severely diminished in HD cells. Inhibitors of ataxia telangiectasia mutated (ATM) kinase decreasedmanganese-dependent phosphorylation of p53. Likewise, analysis of ATMautophosphorylation and additional ATMkinase targets,H2AXandCHK2, support a role forATMin the activation of p53 bymanganese and that a defect in this process occurs in HD. Furthermore, the deficit inMn-dependent activation of ATMkinase in HD neuroprogenitorswas highly selective, as DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits.We assessed cellular manganese handling to test for correlations with the ATM-p53 pathway, and we observed reduced Mn accumulation in HD human neuroprogenitors andHDmouse striatal cells atmanganese exposures associatedwith altered p53 activation. To determine if this phenotype contributes to the deficit in manganese-dependent ATM activation, we used pharmacological manipulation to equalizemanganese levels between HD and control mouse striatal cells and rescued the ATM-p53 signaling deficit. Collectively, our data demonstrate selective alterations in manganese biology in cellular models of HD manifest in ATM-p53 signaling.

Original languageEnglish (US)
Pages (from-to)1929-1944
Number of pages16
JournalHuman molecular genetics
Volume24
Issue number7
DOIs
StatePublished - Oct 28 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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