Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic

Abstract

Cu/Zn superoxide dismutase (SOD1) is a frontline antioxidant enzyme catalysing superoxide breakdown and is important for most forms of eukaryotic life. The evolution of aerobic respiration by mitochondria increased cellular production of superoxide, resulting in an increased reliance upon SOD1. Consistent with the importance of SOD1 for cellular health, many human diseases of the central nervous system involve perturbations in SOD1 biology. But far from providing a simple demonstration of how disease arises from SOD1 loss‐of‐function, attempts to elucidate pathways by which atypical SOD1 biology leads to neurodegeneration have revealed unexpectedly complex molecular characteristics delineating healthy, functional SOD1 protein from that which likely contributes to central nervous system disease. This review summarises current understanding of SOD1 biology from SOD1 genetics through to protein function and stability.

Copper-ATSM as a Treatment for ALS: Support from Mutant SOD1 Models and Beyond

“…Some ALS-causing mutations in SOD1 affect the enzyme's dismutase activity whereas others do not [63,64]. Copper is required for the enzyme's dismutase activity [65].…”

“…Nascent SOD1 contains no metal ions, but through the acquisition of zinc and then copper, apo-SOD1 is converted to its physiological, metal-replete holo form. Holo-SOD1 is a highly stable protein [64]. High levels of transgene expression in SOD1 mouse models are associated with perturbations in the natural abundance of copper (and zinc), including evidence for elevated copper levels in the affected CNS [66,67].…”

Simultaneous structural and elemental nano-imaging of human brain tissue

“…Mature wildtype SOD1 normally binds one Cu and one Zn ion per monomer (1 : 1 ratio) to form a functional and stable homodimer. 9 Reduced Zn 2+ and Cu +/2+ binding to SOD1 plays a crucial role in the misfolding of this protein, and subsequent neurotoxicity in SOD1-associated fALS. 3 Altered Zn 2+ and Cu +/2+ binding to wildtype SOD1 is also suggested to be involved in similar pathogenic pathways in sporadic ALS, 35 consistent with aggregation of wildtype SOD1 in PD.…”

“…8 SOD1 is a homodimeric antioxidant protein that requires Cu and Zn binding in a 1 : 1 ratio for structural stability and normal enzymatic activity. 9 Altered metalation of SOD1 is implicated not only in protein misfolding, but in a toxic gain-offunction of SOD1 protein that is associated with neuronal death. 3 In the PD brain, SOD1 antioxidant activity is reduced specically in the degenerating SN, 8 a change thought to result from altered SOD1 protein metalation.…”

Structural effects of stabilization and complexation of a zinc-deficient superoxide dismutase

“…Recently there is a consensus of the enzyme neurotoxicity and its involvement in neurological diseases not only by a simple loss-of-function, as extensively reviewed by Trist et al. [ 8 ]. One of the first neurotoxic functions of SOD1 was detected in motor neurons when mutations in the enzyme could lead to ALS [ 9 , 10 , 11 ].…”