Activation of AMP-activated protein kinase in cerebella of Atm-/- mice is attributable to accumulation of reactive oxygen species.

Abstract

Ataxia telangiectasia (A-T) is an inherited disease, the most prominent feature of which is ataxia caused by degeneration of cerebellar neurons and synapses. The mechanisms underlying A-T neurodegeneration are still unclear, and many factors are likely to be involved. AMP-activated protein kinase (AMPK) is a sensor of energy balance, and research on its function in neural cells has gained momentum in the last decade. The dual roles of AMPK in neuroprotection and neurodegeneration are complex, and they need to be identified and characterized. Using an Atm (ataxia telangiectasia mutated) gene deficient mouse model, we showed here that: (a) upregulation of AMPK phosphorylation and elevation of reactive oxygen species (ROS) coordinately occur in the cerebella of Atm-/- mice; (b) hydrogen peroxide induces AMPK phosphorylation in primary mouse cerebellar astrocytes in an Atm-independent manner; (c) administration of the novel antioxidant monosodium luminol (MSL) to Atm-/- mice attenuates the upregulation of both phosphorylated-AMPK (p-AMPK) and ROS, and corrects the neuromotor deficits in these animals. Together, our results suggest that oxidative activation of AMPK in the cerebellum may contribute to the neurodegeneration in Atm-/- mice, and that ROS and AMPK signaling pathways are promising therapeutic targets for treatment of A-T and other neurodegenerative diseases.

• Authors: Xianghong Kuang, Mingshan Yan, Joanne M Ajmo, Virginia L Scofield, George Stoica, Paul K Y Wong
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 418 Issue 2 Pg. 267-72 (Feb 10 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 22260947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Cell Cycle Proteins
• DNA-Binding Proteins
• Phthalazines
• Reactive Oxygen Species
• Tumor Suppressor Proteins
• Luminol
• AMPK alpha1 subunit, mouse
• Ataxia Telangiectasia Mutated Proteins
• Atm protein, mouse
• Protein Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• sodium luminolate

Topics

• AMP-Activated Protein Kinases (biosynthesis)
• Animals
• Antioxidants (administration & dosage)
• Ataxia Telangiectasia (enzymology, genetics, pathology)
• Ataxia Telangiectasia Mutated Proteins
• Cell Cycle Proteins (genetics)
• Cerebellum (enzymology, pathology)
• DNA-Binding Proteins (genetics)
• Disease Models, Animal
• Heredodegenerative Disorders, Nervous System (enzymology, genetics, pathology)
• Luminol (analogs & derivatives)
• Mice
• Mice, Mutant Strains
• Mutation
• Oxidative Stress (drug effects)
• Phthalazines (administration & dosage)
• Protein Serine-Threonine Kinases (genetics)
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Tumor Suppressor Proteins (genetics)