Analysis of gain of toxicity induced by amyotrophic lateral sclerosis-linked SOD1 mutants
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Oxidative Modifications of Cu, Zn-Superoxide Dismutase (SOD1) -The Relevance to Amyotrophic Lateral Sclerosis (ALS) 307 ConclusionThe findings mentioned above indicate that oxidative modification of SOD1 at cysteine residues is a critical factor to contribute to the oxidative stress, inclusion pathology and degeneration of motor neurons commonly to familial and sporadic ALS.Based on them, steric inhibition of cysteine oxidation, monomerization or exposure of the dimer interface can be the first-line treatment strategy of this incurable disease.9.
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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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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that involves mainly the motor neuron system. Five to 10 percent of the ALS cases are familial; most others are sporadic. Several mutations in the superoxide dismutase‐1 (SOD1) gene have recently been shown to be associated with about 20% of familial ALS patients. The reduced enzyme activity of many mutant SOD1 points to the possibility that a loss‐of‐function effect of the mutant enzyme is responsible for the pathogenesis of the disease. However, this conflicts with the autosomal dominant inheritance of SOD1 mutation‐associated ALS and the normal SOD1 activity in homozygous patients in a SOD1‐linked ALS family. Current biochemical investigations have provided evidence that mutant SOD1 may catalyze the peroxynitrite‐mediated nitration of protein tyrosine residues, release copper and zinc ions, facilitate apoptosis of neurons and have enhanced peroxidase activity. Immunocytochemical studies demonstrated the presence of intense SOD1 immunoreactivity in Lewy body‐like inclusions, which are characteristic features of a certain form of familial ALS with posterior column involvement, in the lower motor neurons of patients in ALS families with different SOD1 mutations. More recently, strains of transgenic mice expressing mutant SOD1 have been established. These mice clinicopathologically develop a motor neuron disease mimicking human ALS with the exception of pronounced intraneuronal vacuolar degeneration. The overexpression of wild‐type SOD1 in mice has failed to give rise to the disease. Only one transgene for mutant SOD1 is enough to cause motor neuron degeneration and the severity of clinical course correlates with the transgene copy number. These observations in SOD1‐linked familial ALS and its transgenic mouse model suggest a novel neurotoxic function of mutant SOD1.
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OBJECTIVE: Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations.METHODS: Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations.RESULTS: One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease‐associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S59I, V87A, T88ΔTAD, A89T, V97M, S105ΔSL, V118L, D124G, G141X, G147R, I151S) were found, bringing the total number of SOD1 gene mutations in ALS to 105.CONCLUSIONS: Mutations in the SOD1 gene are found both in sporadic and familial ALS cases without any definite predilection for any part of the gene. A common structural denominator for the 16 novel mutations or previously reported mutations is not obvious. Similarly, the nature of the putative acquired toxic function of mutant SOD1 remains unresolved. We conclude that patients with SOD1 mutations may infrequently show symptoms and signs unrelated to the motor systems, sometimes obscuring the diagnosis of ALS.
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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.
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