Impact of the Amyotrophic Lateral Sclerosis Disease on the Biomechanical Properties and Oxidative Stress Metabolism of the Lung Tissue Correlated With the Human Mutant SOD1G93A Protein Accumulation

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, and ALS incidence is increasing worldwide. Patients with ALS have respiratory failure at the disease’s end stages, leading to death; thus, the lung is one of the most affected organs during disease progression. Tissue stiffness increases in various lung diseases because of impaired extracellular matrix (ECM) homeostasis leading to tissue damage and dysfunction at the end. According to the literature, oxidative stress is the major contributor to ECM dysregulation, and mutant protein accumulation in ALS have been reported as causative to tissue damage and oxidative stress. In this study, we used SOD1G93A and SOD1WT rats and measured lung stiffness of rats by using a custom-built stretcher, where H&E staining is used to evaluate histopathological changes in the lung tissue. Oxidative stress status of lung tissues was assessed by measuring glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6-PGD), glutathione reductase (GR), glutathione s-transferase (GST), catalase (CAT), and superoxide dismutase 1 (SOD1) levels. Western blot experiments were performed to evaluate the accumulation of the SOD1G93A mutated protein. As a result, increased lung stiffness, decreased antioxidant status, elevated levels of oxidative stress, impaired mineral and trace element homeostasis, and mutated SOD1G93A protein accumulation have been found in the mutated rats even at the earlier stages, which can be possible causative of increased lung stiffness and tissue damage in ALS. Since lung damage has altered at the very early stages, possible therapeutic approaches can be used to treat ALS or improve the life quality of patients with ALS.

Oxidative stress induced by hydrogen peroxide disrupts zebrafish visual development by altering apoptosis, antioxidant and estrogen related genes

“…Elevated ROS production induces adverse effects on crucial cellular structures, including proteins, lipids, and nucleic acids 21 . Evidence suggests oxidative stress's involvement in various diseases, including cancer, diabetes, metabolic disorders, atherosclerosis, endocrine dysfunction, infertility, neurological, and cardiovascular diseases 22 – 24 .…”

The possible role of the endocrine disrupting chemicals on the premature and early menopause associated with the altered oxidative stress metabolism

“…On the other hand, GPx and CAT detoxify hydrogen peroxide (H 2 O 2 ), where SOD breaks down superoxide (O 2.- ) into water (H 2 O 2 ) ( 11 – 13 ). Impaired oxidative stress status has been reported in the pathogenesis of various diseases such as cancer, diabetes, metabolic disorders, endocrine dysfunction, cardiovascular diseases, infertility, and neurological diseases, since ROS attack the DNA, lipid, proteins, and nucleic acids ( 14 , 15 ). On the other hand, oxidative stress affects follicular fluid, oocyte maturation, ovarian steroid biosynthesis, ovulation, formation of blastocysts, implantation, embryogenesis, miscarriage, early birth, ovarian germ cell, and pre‐eclampsia, according to the literature ( 16 ).…”

Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?

“…The accumulation of mutant SOD1 proteins in ALS could be the cause of tissue damage and OS. For example, in the SOD1G93A mouse model, mutated-protein accumulation in the mitochondria and cytosol causes impaired energy metabolism and OS in the lungs, with the lower activity of antioxidant enzymes, such as glutathione reductase or catalase [ 55 ]. In addition to the loss of function of antioxidant enzymes, mutations in SOD1 reduce the protein-folding stability through the disruption of metal binding and/or disulfide-bond formation, resulting in misfolding, aggregation and ultimately cell toxicity [ 56 ].…”