SOD1 in ALS: Taking Stock in Pathogenic Mechanisms and the Role of Glial and Muscle Cells

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons in the brain and spinal cord. While the exact causes of ALS are still unclear, the discovery that familial cases of ALS are related to mutations in the Cu/Zn superoxide dismutase (SOD1), a key antioxidant enzyme protecting cells from the deleterious effects of superoxide radicals, suggested that alterations in SOD1 functionality and/or aberrant SOD1 aggregation strongly contribute to ALS pathogenesis. A new scenario was opened in which, thanks to the generation of SOD1 related models, different mechanisms crucial for ALS progression were identified. These include excitotoxicity, oxidative stress, mitochondrial dysfunctions, and non-cell autonomous toxicity, also implicating altered Ca2+ metabolism. While most of the literature considers motor neurons as primary target of SOD1-mediated effects, here we mainly discuss the effects of SOD1 mutations in non-neuronal cells, such as glial and skeletal muscle cells, in ALS. Attention is given to the altered redox balance and Ca2+ homeostasis, two processes that are strictly related with each other. We also provide original data obtained in primary myocytes derived from hSOD1(G93A) transgenic mice, showing perturbed expression of Ca2+ transporters that may be responsible for altered mitochondrial Ca2+ fluxes. ALS-related SOD1 mutants are also responsible for early alterations of fundamental biological processes in skeletal myocytes that may impinge on skeletal muscle functions and the cross-talk between muscle cells and motor neurons during disease progression.

Expression of the H2O2 Biosensor roGFP-Tpx1.C169S in Fission and Budding Yeasts and Jurkat Cells to Compare Intracellular H2O2 Levels, Transmembrane Gradients, and Response to Metals

“…This enzyme is essential to dismutating superoxide anion into H 2 O 2 and oxygen, and it is located in the cytosol and the intermembrane mitochondrial space [ 40 , 41 ]. Mutations in the gene coding for Sod1 are linked to amyotrophic lateral sclerosis (ALS), probably through the effect of mutations on the cellular proteostatic balance [ 42 , 43 ]. The concentration of Sod1 in S. pombe, based on quantitative analysis of the fission yeast proteome, is very high under basal conditions, in the order of 4–5 µM [ 44 ].…”

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases

“…The author showed that in both sporadic and familial ALS, mutations in autophagy gene were found. SOD1 was the first gene whose mutations were linked to ALS account accounting for about 3% of total ALS cases with more than 180 mutations discovered thus far linked to ALS ( Peggion et al, 2022 ).…”

“…The author showed that in both sporadic and familial ALS, mutations in autophagy gene were found. SOD1 was the first gene whose mutations were linked to ALS account accounting for about 3% of total ALS cases with more than 180 mutations discovered thus far linked to ALS (Peggion et al, 2022). The accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the primary clinical signature in all cases of ALS.…”

Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival

“…The earliest discovered genetic predisposition in ALS was found in Cu/Zn superoxide dismutase 1 (SOD1). Mutations in SOD1 make up approximately 20% of all fALS cases and are identified in 2–7% of sALS cases [ 10 ]. In 1994, Gurney et al [ 11 ] created the first transgenic mouse model for ALS, the tg(SOD1*G93A)1Gur mice that develop ALS-like symptoms, by introducing a high copy number of the human mutated SOD1 gene (SOD1*G93A) into the mice’s genome.…”