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

Yoshiaki Furukawa,Eiichi Tokuda

doi:10.1186/s40035-020-00209-y

Yoshiaki Furukawa, Eiichi Tokuda

Open Access

https://doi.org/10.1186/s40035-020-00209-y

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Journal: Translational neurodegeneration	Publication Date: Aug 19, 2020
Citations: 24	License type: open-access

Affiliation: Keio University, Nihon University

Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease classically characterized by loss of motor neurons in the central nervous system including motor cortex, brainstem, and spinal cord [1]
cerebrospinal fluid (CSF) collected from ALS patients has been known to exert toxicity toward motorneuron like cells NSC-34 [99], and we revealed that the toxicity was alleviated by removing the misfolded SOD1 from CSF with immunoprecipitation using C4F6
Xu et al suggested the oxidation of Cys111 in SOD1 to a sulfenic acid (−SOH) in CSF of a subset of sporadic ALS cases [103], and we found that Cys111 was oxidized to a sulfonic acid (−SO3H) in CSF of a subset of ALS, Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and AD cases [95]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease classically characterized by loss of motor neurons in the central nervous system including motor cortex, brainstem, and spinal cord [1]. Even in the absence of ALS-causing mutant SOD1, overexpression of wild-type human SOD1 alone can exert motor neuron toxicity to mice.

Results

Conclusion