An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1

Weinberg Unit for ALS Research, Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2012; 109(13):5074-9. DOI: 10.1073/pnas.1115402109
Source: PubMed


Recent studies suggest that Cu/Zn superoxide dismutase (SOD1) could be pathogenic in both familial and sporadic amyotrophic lateral sclerosis (ALS) through either inheritable or nonheritable modifications. The presence of a misfolded WT SOD1 in patients with sporadic ALS, along with the recently reported evidence that reducing SOD1 levels in astrocytes derived from sporadic patients inhibits astrocyte-mediated toxicity on motor neurons, suggest that WT SOD1 may acquire toxic properties similar to familial ALS-linked mutant SOD1, perhaps through posttranslational modifications. Using patients' lymphoblasts, we show here that indeed WT SOD1 is modified posttranslationally in sporadic ALS and is iper-oxidized (i.e., above baseline oxidation levels) in a subset of patients with bulbar onset. Derivatization analysis of oxidized carbonyl compounds performed on immunoprecipitated SOD1 identified an iper-oxidized SOD1 that recapitulates mutant SOD1-like properties and damages mitochondria by forming a toxic complex with mitochondrial Bcl-2. This study conclusively demonstrates the existence of an iper-oxidized SOD1 with toxic properties in patient-derived cells and identifies a common SOD1-dependent toxicity between mutant SOD1-linked familial ALS and a subset of sporadic ALS, providing an opportunity to develop biomarkers to subclassify ALS and devise SOD1-based therapies that go beyond the small group of patients with mutant SOD1.

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    • "The nature of the toxic activity mediated by astrocytes, and the mechanisms of MN death that they trigger, remain unclear even in the rodent mutSOD1 systems, yet their identification has the potential to reveal new therapeutic targets. One candidate toxic factor in sALS was SOD1 itself, given that misfolded wtSOD1 is enriched in MNs of some sALS patients (Bosco et al., 2010; Guareschi et al., 2012). In keeping with this possibility, Haidet- Phillips et al. (2011) reported that silencing SOD1 in hNPC-astrocytes from sALS patients (hence without SOD1 mutations) did attenuate the loss of mES-MNs. "
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    ABSTRACT: Most cases of neurodegenerative diseases are sporadic, hindering the use of genetic mouse models to analyze disease mechanisms. Focusing on the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS), we therefore devised a fully humanized coculture model composed of human adult primary sporadic ALS (sALS) astrocytes and human embryonic stem-cell-derived MNs. The model reproduces the cardinal features of human ALS: sALS astrocytes, but not those from control patients, trigger selective death of MNs. The mechanisms underlying this non-cell-autonomous toxicity were investigated in both astrocytes and MNs. Although causal in familial ALS (fALS), SOD1 does not contribute to the toxicity of sALS astrocytes. Death of MNs triggered by either sALS or fALS astrocytes occurs through necroptosis, a form of programmed necrosis involving receptor-interacting protein 1 and the mixed lineage kinase domain-like protein. The necroptotic pathway therefore constitutes a potential therapeutic target for this incurable disease.
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    • "It is intriguing that the H 2 O 2 product of the dismutation reaction that is catalyzed by SOD1 (Figure 2) can also induce the conversion of this otherwise normal protein into a misfolded, toxic species (Ezzi et al., 2007; Bosco et al., 2010). A report by Guareschi et al., may shed some light onto the nature of the SOD1 modifications in vivo, as elevated levels of carbonylated SOD1 species were detected in lymphoblast cell lines from a subset of SALS patients with bulbar onset (Guareschi et al., 2012). An overoxidized form of WT SOD1 that could explain both SOD1 misfolding and toxicity in SALS is reasonable, considering that oxidative stress is a pathological hallmark of SALS (D'Amico et al., 2013). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that targets motor neurons, leading to paralysis and death within a few years of disease onset. While several genes have been linked to the inheritable, or familial, form of ALS, much less is known about the cause(s) of sporadic ALS, which accounts for ~90% of ALS cases. Due to the clinical similarities between familial and sporadic ALS, it is plausible that both forms of the disease converge on a common pathway and, therefore, involve common factors. Recent evidence suggests the Cu,Zn-superoxide dismutase (SOD1) protein to be one such factor that is common to both sporadic and familial ALS. In 1993, mutations were uncovered in SOD1 that represent the first known genetic cause of familial ALS. While the exact mechanism of mutant-SOD1 toxicity is still not known today, most evidence points to a gain of toxic function that stems, at least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, non-genetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a "toxic conformation" that is similar to familial ALS-linked SOD1 variants. These observations, together with the detection of misfolded wild-type SOD1 within human post-mortem sporadic ALS samples, have been used to support the controversial hypothesis that misfolded forms of wild-type SOD1 contribute to sporadic ALS pathogenesis. In this review, we present data from the literature that both support and contradict this hypothesis. We also discuss SOD1 as a potential therapeutic target for both familial and sporadic ALS.
    Full-text · Article · Dec 2013 · Frontiers in Cellular Neuroscience
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    • "Derivatization analysis of oxidized carbonyl compounds performed on immunoprecipitated SOD1 identified a hyper-oxidized SOD1 that recapitulates mutant SOD1-like properties and damages mitochondria by forming a toxic complex with Bcl-2. Guareschi et al., 2012 The mean protein carbonyl level in the lumbar spinal cord from patients with sporadic motor neuron disease was increased by 119% (p b 0.02) when compared to normal control subjects and by 88% (p b 0.04) compared to the neurological disease control subjects. Shaw et al., 1995 Protein carbonyl and 8-OHdG levels were increased in sporadic ALS but not in autosomal dominant familial ALS patients. "
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    ABSTRACT: Oxidative stress is a common hallmark of neuronal cell death associated with neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, as well as brain stroke/ischemia and traumatic brain injury. Increased accumulation of reactive species of both oxygen (ROS) and nitrogen (RNS) has been implicated in mitochondrial dysfunction, energy impairment, alterations in metal homeostasis and accumulation of aggregated proteins observed in neurodegenerative disorders, which lead to the activation/modulation of cell death mechanisms that include apoptotic, necrotic and autophagic pathways. Thus, the design of novel antioxidant strategies to selectively target oxidative stress and redox imbalance might represent important therapeutic approaches against neurological disorders. This work reviews the evidence demonstrating the ability of genetically encoded antioxidant systems to selectively counteract neuronal cell loss in neurodegenerative diseases and ischemic brain damage. Because gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches, we discussed basic research/clinical evidence and the potential of virus-mediated gene delivery techniques for antioxidant gene therapy.
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