The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Abstract

Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

“…As a result of being the first protein found to harbor ALS-associated mutations (Rosen et al, 1993 ), SOD1, in its purified form, has been extensively studied from the perspectives of protein folding, aggregation, and prion-like propagation (McAlary et al, 2019b ; Wright et al, 2019 ; Trist et al, 2020 ). SOD1 protein is most often expressed and purified using either bacteria ( E. coli ) or yeast ( S. cerevisiae , Hallewell et al, 1985 , 1987 ).…”

“…A SOD1 monomer is an 8-stranded β-barrel with two major loops, the metal-binding loop (loop IV) and electrostatic loop (loop VII), being responsible for the coordination of metals or guidance of superoxide substrate to the enzymatic site, respectively. Furthermore, a conserved intramolecular disulfide, that stabilizes the tertiary structure and promotes dimerization, is formed between residues Cys57 and Cys146 (Wright et al, 2019 ). The native conformation of SOD1 is an impressively stable homodimer, evidenced by resistance to thermal denaturation and proteolytic digestion (Senoo et al, 1988 ; Rodriguez et al, 2002 ).…”

Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases

“…There is an increment of glucose catabolic activity upstream of the mitochondrial aerobic respiration in SOD1G93A mice, indicating that mitochondrial dynamics represent the crucial site of the synaptic bioenergetic impairment in ALS (Ravera et al, 2019). Superoxide dismutase 1 mutations affect protein folding, which is a potential source of the toxicity that leads to mitochondria degeneration (Wright et al, 2019). Misfolded proteins aggregate within the intermembrane space of mitochondria, ultimately leading to membrane disruption (Salehi et al, 2015;Watanabe et al, 2016).…”

Molecular and pharmacological chaperones for SOD1

“…An absence of post-translation modifications would, therefore, be necessary for this binding site to be exposed. While β-strand 7 is not a structured component of SOD1 aggregates, reviewed [8], it is part of the folding nucleus that orchestrates SOD1 β-barrel formation [1]. Thus, the timely termination of this interaction is exceptionally important.…”

“…Roughly two-thirds of SOD1 amino acids have been shown to harbour ALS-related mutations and, in general, they are found in conserved metal binding, interface and β-barrel residues. Each mutation diminishes the likelihood SOD1 will progress along its maturation pathway to populate stable and folded states (Figure 1) but the molecular and phenotypic manifestations of individual mutations can vary, reviewed [8].…”