RELATIONSHIP OF OXYGEN RADICAL-INDUCED LIPID PEROXIDATIVE DAMAGE TO DISEASE ONSET AND PROGRESSION IN A TRANSGENIC MODEL OF FAMILIAL ALS

Transgenic mice that overexpress a mutated human CuZn superoxide dismu tase (SOD1) gene (gly(93)-->ala) found in some patients with familial ALS (FALS) have been shown to develop motor neuron disease, as evidenc ed by motor neuron loss in the lumbar and cervical spinal regions and a progressive loss of voluntary motor activity. The mutant Cu,Zn SOD e xhibits essentially normal dismutase activity, but in addition, genera tes toxic oxygen radicals as a result of an enhancement of a normally minor peroxidase reaction. In view of the likelihood that the manifest ation of motor neuron disease in the FALS transgenic mice involves an oxidative injury mechanism, the present study sought to examine the ex tent of lipid peroxidative damage in the spinal cords of the TgN(SOD1- G93A)G1H mice over their life span compared to nontransgenic littermat es or transgenic mice that overexpress the wild-type human Cu,Zn SOD ( TgN(SOD1)N29), Lipid peroxidation was investigated in terms of changes in vitamin E and malondialdehyde (MDA) levels measured by HPLC method s and by MDA-protein adduct immunoreactivity, Four ages were investiga ted: 30 days (pre-motor neuron pathology and clinical disease); 60 day s (after initiation of pathology, but predisease); 100 days (approxima tely 50% loss of motor neurons and function); and 120 days (near compl ete hindlimb paralysis). Compared to nontransgenic mice, the TgN(SOD1G 93A)G1H mice showed blunted accumulation of spinal cord vitamin E and higher levels of MDA (P < 0.05 at 30 and 60 days) over the 30-120 day time span, In the TgN(SOD1)N29 mice, levels of MDA at age 120 days wer e significantly lower than in either the TgN(SOD1-G93A)G1H or nontrans genic mice, MDA-protein adduct immunoreactivity was also significantly Increased in the lumbar spinal cord at age 30, 100, and 120 days, and in the cervical cord at 100 and 120 days, The results clearly demonst rate an increase in spinal cord lipid peroxidation in the FALS transge nic model, which precedes the onset of ultrastructural or clinical mot or neuron disease, However, the greatest intensity of actual motor neu ronal lipid peroxidative injury is associated with the active phase of disease progression, These findings further support a role of oxygen radical-mediated motor neuronal injury in the pathogenesis of FALS and the potential benefits of antioxidant therapy, J, Neurosci, Res, 53:6 6-77, 1998, (C) 1998 Wiley-Liss,Inc.