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 journalArticle

28 Citations (Scopus)

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)
Article numberddu609
Pages (from-to)1929-1944
Number of pages16
JournalHuman Molecular Genetics
Volume24
Issue number7
DOIs
StatePublished - Oct 28 2014

Fingerprint

Corpus Striatum
Ataxia Telangiectasia
Huntington Disease
Manganese
Phosphorylation
Micronutrients
Basal Ganglia
Serine
DNA Damage
Cell Biology
Phosphotransferases
Pharmacology
Phenotype
Cell Line
Wounds and Injuries
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease. / Tidball, Andrew M.; Bryan, Miles R.; Uhouse, Michael A.; Kumar, Kevin K.; Aboud, Asad A.; Feist, Jack E.; Ess, Kevin C.; Diana Neely, M.; Aschner, Michael; Bowman, Aaron B.

In: Human Molecular Genetics, Vol. 24, No. 7, ddu609, 28.10.2014, p. 1929-1944.

Research output: Contribution to journalArticle

Tidball, AM, Bryan, MR, Uhouse, MA, Kumar, KK, Aboud, AA, Feist, JE, Ess, KC, Diana Neely, M, Aschner, M & Bowman, AB 2014, 'A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease', Human Molecular Genetics, vol. 24, no. 7, ddu609, pp. 1929-1944. https://doi.org/10.1093/hmg/ddu609
Tidball, Andrew M. ; Bryan, Miles R. ; Uhouse, Michael A. ; Kumar, Kevin K. ; Aboud, Asad A. ; Feist, Jack E. ; Ess, Kevin C. ; Diana Neely, M. ; Aschner, Michael ; Bowman, Aaron B. / A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease. In: Human Molecular Genetics. 2014 ; Vol. 24, No. 7. pp. 1929-1944.
@article{05922fe4adfe449aa7d8ba5d15765d16,
title = "A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease",
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.",
author = "Tidball, {Andrew M.} and Bryan, {Miles R.} and Uhouse, {Michael A.} and Kumar, {Kevin K.} and Aboud, {Asad A.} and Feist, {Jack E.} and Ess, {Kevin C.} and {Diana Neely}, M. and Michael Aschner and Bowman, {Aaron B.}",
year = "2014",
month = "10",
day = "28",
doi = "10.1093/hmg/ddu609",
language = "English (US)",
volume = "24",
pages = "1929--1944",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease

AU - Tidball, Andrew M.

AU - Bryan, Miles R.

AU - Uhouse, Michael A.

AU - Kumar, Kevin K.

AU - Aboud, Asad A.

AU - Feist, Jack E.

AU - Ess, Kevin C.

AU - Diana Neely, M.

AU - Aschner, Michael

AU - Bowman, Aaron B.

PY - 2014/10/28

Y1 - 2014/10/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84926435051&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926435051&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu609

DO - 10.1093/hmg/ddu609

M3 - Article

C2 - 25489053

AN - SCOPUS:84926435051

VL - 24

SP - 1929

EP - 1944

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 7

M1 - ddu609

ER -