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The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids

DANXIA LIU^*,1, JING WEN^*, JING LIU^* and LIPING LI^*

Departments of
^* Neurology and
Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555-0653, USA

¹Correspondence: Gail Borden Bldg., Route 0653, Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555-0653, USA. E-mail: DLiu{at}utmb.edu

To explore whether reactive oxygen species (ROS) play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a unique microdialysis or microcannula sampling technique was used in mice transfected with a mutant Cu,Zn-superoxide dismutase (SOD1) gene from humans with familial ALS, mice transfected with the normal human SOD1 gene, and normal mice. We demonstrate for the first time that the levels of hydrogen peroxide (H₂O₂) and the hydroxyl radical (^·OH) are significantly higher, and the level of the superoxide anion (O₂^·-) is significantly lower in ALS mutant mice than in controls, supporting by in vivo evidence the hypothesis that the mutant enzyme catalyzes ^·OH formation by the sequence: O₂^·- H₂O₂ ^·OH. This removes doubts regarding the relevance of elevated ROS in FALS raised by in vitro experiments. The levels of oxidation products are also significantly higher in the mutant mice than in controls, consistent with some previous reports. Only the superoxide concentration differs between two controls among all the measurements. Our findings correlate in vivo a gene mutation to both elevated H₂O₂ and ^·OH and increased oxidation of cellular constituents. The elevated H₂O₂ in mutant mice indicates impairment of its detoxification pathways, perhaps by changed interactions between SOD1 and H₂O₂ detoxification enzymes.—Liu, D., Wen, J., Liu, J., Li, L. The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids.

Key Words: mutation of Cu,Zn-superoxide dismutase gene • transgenic mouse • hydrogen peroxide • hydroxyl radical • superoxide anion

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