Targeting the mutant SOD1G93A protein-induced oxidative stress in the central nervous system and peripheral tissues can be a promising therapeutic approach in als disease

Abstract

Background: ALS is the most common motor neuron disease, and the incidence of the disease is increasing worldwide. Since there is no effective treatment for ALS, urgent therapeutic approaches are required to cure the disease. 1–3 . Aim: We investigated oxidative stress metabolism and antioxidant capacity of the central nervous system and peripheral tissues at the pre-symptomatic and Abstracts Free Radical Biology and Medicine 201 (2023) 1–64 57 symptomatic stages of ALS. Method: SOD1G93A mutated albino male rats were used for the experiments. Histopathological, molecular, and biochemical examinations of the brain, spinal cord, testis, spleen, liver, kidney, and heart tissues were performed. H&E, OLIG2, and myelin staining were performed to evaluate histopathological changes. Mitochondrial and cytosolic fractions of the tissues were prepared and used for the biochemical and molecular evaluation. Glucose-6 phosphate dehydrogenase (G6PD), 6-phosphoglucanate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione-s transferase (GST), catalase (CAT), superoxide dismutase 1 (SOD1), isocitrate dehydrogenase 1,2,3 (IDH1,2,3) were evaluated in all tissues. Human mutant SOD1G93A protein accumulation in the tissues was assessed via western blot. Results: Cytosolic and mitochondrial G6PD, 6-PGD, GR, GST, CAT, SOD1, IDH1, IDH2, and IDH3 enzyme activities were impaired in the SOD1G93A mutated rats compared to the wild-type rats of each group in all tissues. OLIG2 expression increased in the central nervous system of the ALS rats, where histopathological alterations were observed in all SOD1G93A rats. Additionally, SOD1G93A protein aggregation was observed in the cytosol and mitochondria of all tissues at the pre-symptomatic and symptomatic stages. Conclusion: Oxidative stress metabolism and pentose phosphate pathway (PPP) have been impaired because of human mutant SOD1G93A protein accumulation in ALS rats that result in histopathological changes in all tissues. Therefore, targeting oxidative stress metabolism and PPP can be promising therapeutic targets to cure people with ALS in the future.