SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disorder that is characterized by the selective death of motor neurons. While the fundamental cause of the disorder is still unclear, the first identified risk gene, Cu,Zn superoxide dismutase (SOD1), has led to the proposal of several mechanisms that are relevant to its pathogenesis. These include excitotoxicity, oxidative stress, ER stress, mitochondrial dysfunction, axonal transport disruption, prion-like propagation, and non-cell autonomous toxicity of neuroglia. Recent evidence suggests that the toxicity of the misfolded wild-type SOD1 (SOD1^WT) is involved in the pathogenesis of sporadic cases. Yet to what extent SOD1 contributes to neurotoxicity in ALS cases generally is unknown. This review discusses the toxic mechanisms of mutant SOD1 (SOD1^mut) and misfolded SOD1^WT in the context of ALS as well as the potential implication of these mechanisms in SOD1 mutation-negative ALS.

Introduction

Amyotrophic lateral sclerosis (ALS) is one of the most common neuromuscular diseases worldwide. Ever since the disease was named by neurobiologist and physician Jean-Martin Charcot in 1874, ALS has been a grave health threat due to its relentless progression (Oliveira and Pereira, 2009). Most ALS cases appear in mid-life and provoke a selective loss of upper and lower motor neurons, which eventually results in death by respiratory failure. However, only a few methods or ideas have been applied to combat ALS in the century since it was first described. Additionally, its etiologic study has been relatively slow. Only recently has a broader understanding of the cause of ALS begun to quickly emerge.

In 1993, the identification of the SOD1 gene encoding Cu,Zn superoxide dismutase as a primary cause of ALS accelerated ALS research (Rosen et al., 1993). Now, more than 180 mutations have been associated with ALS and almost all of these mutations are inherited in an autosomal dominant manner (Abel et al., 2012; http://alsod.iop.kcl.ac.uk/). Approximately 10% of all cases are familial, of which SOD1 is estimated to account for 20% (Fig. 1). Loss or gain of dismutase activity was initially assumed to be the mechanism of SOD1 mutation toxicity. Regarding this point, an early study demonstrated that clinical severity did not correlate with SOD1 dismutase activity (Cleveland et al., 1995). Moreover, transgenic mice that overexpressed the ALS-linked SOD1 G93A mutant exhibited ALS-like phenotypes, while SOD1 deficient mice did not (Gurney et al., 1994, Reaume et al., 1996). Together, these reports support a gain of toxic function mechanism of SOD1^mut.

In recent years, ALS research has experienced a paradigm shift. The identification of mutations in a pair of RNA/DNA binding proteins, TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS), implicated RNA toxicity in ALS, because their principal physiological functions include RNA processing, such as splicing, transport, and translation (Sreedharan et al., 2008, Kwiatkowski et al., 2009, Vance et al., 2009). Furthermore, a newly identified hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) displaced SOD1 as the most frequent causative gene of ALS because C9ORF72 accounts for approximately 38% of familial ALS (FALS) cases (DeJesus-Hernandez et al., 2011, Renton et al., 2011).

Although the broad understanding of ALS has been significantly transformed by these new insights regarding the genetics of ALS, intensive research of SOD1 for 20 years has significantly contributed to the understanding of ALS. Here, we discuss several mechanisms by which SOD1 exerts its toxicity and the possibility of its implications in SALS and SOD1 mutation-negative FALS.