Activation of the Nrf2-ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1.
Oxidative stress plays a key role in the neuronal loss exhibited in amyotrophic lateral sclerosis (ALS), an event precipitating irreversible muscle atrophy. By crossing ALS mouse models (SOD(G93A) and SOD(H46RH48Q)) with an antioxidant response element (ARE) reporter mouse, we identified activation characteristics of the ARE system throughout the timecourse of motor neuron disease. Surprisingly, the earliest and most significant activation of this genetic sensor of oxidative stress occurred in the distal muscles of mutant SOD mice. The resultant data supports existing hypotheses that the muscle is somehow implicated during the initial pathology of these mice. Subsequently, Nrf2-ARE activation appears to progress in a retrograde fashion along the motor pathway. These data provide timely information concerning the contributions of the Nrf2-ARE pathway in ALS disease progression.
Kraft
Andrew D
AD
Division of Pharmaceutical Sciences, Madison, WI, USA.
Resch
Jon M
JM
Johnson
Delinda A
DA
Johnson
Jeffrey A
JA
D000409:Alanine; D000469:Alkaline Phosphatase / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005998:Glycine; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020218:Response Elements; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000469:Alkaline Phosphatase; D000409:Alanine; D005998:Glycine