Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling

Stem Cells. 2009 Aug;27(8):1987-98. doi: 10.1002/stem.125.

Abstract

Ataxia-telangiectasia (A-T) is a genetic disorder caused by a mutation of the Atm gene, which controls DNA repair, cell cycling, and redox homeostasis. Even though oxidative stress has been implicated in the neurological anomalies in A-T, the effects of ATM loss on neural stem cell (NSC) survival has remained elusive. In this study, we investigated the effects of oxidative stress on NSC proliferation in an animal model for A-T neurodegeneration. We found that cultured subventricular zone neurosphere cells from Atm(-/-) mice show impaired proliferation, as well as intrinsic elevation of reactive oxygen species (ROS) levels, compared with those from Atm(+/+) mice. We also show that increasing the levels of ROS by H(2)O(2) treatment significantly reduces Atm(+/+) neurosphere formation and proliferation. In Atm(-/-) neurosphere cells, the Akt and Erk1/2 pathways are disrupted, together with enhanced activity of the p38 mitogen-activated protein kinase (MAPK). Treatment of these cells with the antioxidant N-acetyl-L-cysteine (NAC) or with a p38 MAPK inhibitor restores normal proliferation and reduced expression of p21(cip1) and p27(kip1) in the Atm(-/-) NSCs. These observations indicate that ATM plays a crucial role in NSC proliferation, by activating Akt and Erk1/2 pathways and by suppressing ROS-p38 MAPK signaling. Together, our results suggest that p38 MAPK signaling acts as a negative regulator of NSC proliferation in response to oxidative stress. These findings suggest a potential mechanism for neuronal cell loss as a result of oxidative stress in NSCs in progressive neurodegenerative diseases such as A-T.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics
  • Cell Growth Processes / physiology
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Hydrogen Peroxide / pharmacology
  • MAP Kinase Signaling System
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Oncogene Protein v-akt / metabolism
  • Oxidative Stress / physiology*
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Reactive Oxygen Species / metabolism
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Cdkn1a protein, mouse
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA-Binding Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Hydrogen Peroxide
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Oncogene Protein v-akt
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Acetylcysteine