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

Hilton, James B.; Hare, Dominic J.; Crouch, Peter J.; Double, Kay L.

doi:10.1002/ange.202000451

Cited by 10 publications

(12 citation statements)

References 316 publications

(399 reference statements)

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“…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 ).…”

Section: In Vitro Models To Examine Proteostasis and Prion-lmentioning

confidence: 99%

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

McAlary

Chew

Lum

et al. 2020

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of the motor neurons that innervate muscle, resulting in gradual paralysis and culminating in the inability to breathe or swallow. This neuronal degeneration occurs in a spatiotemporal manner from a point of onset in the central nervous system (CNS), suggesting that there is a molecule that spreads from cell-to-cell. There is strong evidence that the onset and progression of ALS pathology is a consequence of protein misfolding and aggregation. In line with this, a hallmark pathology of ALS is protein deposition and inclusion formation within motor neurons and surrounding glia of the proteins TAR DNA-binding protein 43, superoxide dismutase-1, or fused in sarcoma. Collectively, the observed protein aggregation, in conjunction with the spatiotemporal spread of symptoms, strongly suggests a prion-like propagation of protein aggregation occurs in ALS. In this review, we discuss the role of protein aggregation in ALS concerning protein homeostasis (proteostasis) mechanisms and prion-like propagation. Furthermore, we examine the experimental models used to investigate these processes, including in vitro assays, cultured cells, invertebrate models, and murine models. Finally, we evaluate the therapeutics that may best prevent the onset or spread of pathology in ALS and discuss what lies on the horizon for treating this currently incurable disease.

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Section: In Vitro Models To Examine Proteostasis and Prion-lmentioning

confidence: 99%

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

McAlary

Chew

Lum

et al. 2020

Front. Cell. Neurosci.

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“…Nonetheless, pathological examinations on SOD1-ALS cases provide us with important clues to understand disease mechanisms; namely, SOD1 proteins abnormally accumulate and form inclusions selectively in affected motor neurons [5]. Based upon such pathological observations, furthermore, a mechanism has been proposed where SOD1 proteins assume an abnormal conformation (or misfold) by an amino acid substitution corresponding to a pathogenic mutation, accumulate as oligomers/aggregates, and then exert toxicity to kill motor neurons [6]. Several researchers have attempted to extend the pathological roles of SOD1 misfolding in SOD1-ALS to more prevailing ALS cases, in which no mutations in the SOD1 gene are confirmed (non-SOD1 ALS).…”

Section: Introductionmentioning

confidence: 99%

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Furukawa

Tokuda

2020

Transl Neurodegener

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Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset progressive degeneration of upper and lower motor neurons. Increasing numbers of genes are found to be associated with ALS; among those, the first identified gene, SOD1 coding a Cu/Zn-superoxide dismutase protein (SOD1), has been regarded as the gold standard in the research on a pathomechanism of ALS. Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1 (SOD1-ALS). Nonetheless, involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations (non-SOD1 ALS), which occupies more than 90% of total ALS cases. In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins; therefore, SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases, non-SOD1 ALS. In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo, we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.

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“…The misfolding and aggregation of human SOD1 are correlated to the onset of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. 33 The maturation of human SOD1 and its ALS-related mutants has been extensively characterized by NMR both in vitro 34 − 36 and in human cells. 7 , 8 , 37 In its mature active state, human SOD1 is a stably folded homodimer where each monomer binds one zinc ion and one copper ion, and harbors an intramolecular disulfide bond between C57 and C146 that provides structural stability (Cu,Zn-SOD1 SS ).…”

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confidence: 99%

Real-Time Quantitative In-Cell NMR: Ligand Binding and Protein Oxidation Monitored in Human Cells Using Multivariate Curve Resolution

et al. 2020

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In-cell NMR can investigate protein conformational changes at atomic resolution, such as those changes induced by drug binding or chemical modifications, directly in living human cells, and therefore has great potential in the context of drug development as it can provide an early assessment of drug potency. NMR bioreactors can greatly improve the cell sample stability over time and, more importantly, allow for recording in-cell NMR data in real time to monitor the evolution of intracellular processes, thus providing unique insights into the kinetics of drug-target interactions. However, current implementations are limited by low cell viability at >24 h times, the reduced sensitivity compared to “static” experiments and the lack of protocols for automated and quantitative analysis of large amounts of data. Here, we report an improved bioreactor design which maintains human cells alive and metabolically active for up to 72 h, and a semiautomated workflow for quantitative analysis of real-time in-cell NMR data relying on Multivariate Curve Resolution. We apply this setup to monitor protein–ligand interactions and protein oxidation in real time. High-quality concentration profiles can be obtained from noisy 1D and 2D NMR data with high temporal resolution, allowing further analysis by fitting with kinetic models. This unique approach can therefore be applied to investigate complex kinetic behaviors of macromolecules in a cellular setting, and could be extended in principle to any real-time NMR application in live cells.

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

Cited by 10 publications

References 316 publications

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

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

Does wild-type Cu/Zn-superoxide dismutase have pathogenic roles in amyotrophic lateral sclerosis?

Real-Time Quantitative In-Cell NMR: Ligand Binding and Protein Oxidation Monitored in Human Cells Using Multivariate Curve Resolution

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