Characterization of the activity, aggregation, and toxicity of heterodimers of WT and ALS-associated mutant Sod1

Brasil, Aline de Araújo; Carvalho, Mariana Dias Castela de; Gerhardt, Ellen; Queiroz, Daniela Dias; Pereira, Marcos D.; Outeiro, Tiago F.; Eleuthério, Elis C. A.

doi:10.1073/pnas.1902483116

Cited by 47 publications

(34 citation statements)

References 54 publications

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“…More than 185 SOD1 mutations have already been associated with ALS [ 13 ]. Although these mutations affect different locations within the SOD1 structure [ 16 ], many of them lead to protein-aggregation and increased oxidative damage, which are central events in ALS pathogenicity [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

2021

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Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disorder, with a significant social and economic burden. ALS remains incurable, and the only drugs approved for its treatments confers a survival benefit of a few months for the patients. Missense mutations in superoxide dismutase 1 (SOD1), a major cytoplasmic antioxidant enzyme, has been associated with ALS development, accounting for 23% of its familial cases and 7% of all sporadic cases. This work aims to characterize in silico the structural and functional effects of SOD1 protein variants. Missense mutations in SOD1 were compiled from the literature and databases. Twelve algorithms were used to predict the functional and stability effects of these mutations. ConSurf was used to estimate the evolutionary conservation of SOD1 amino-acids. GROMACS was used to perform molecular dynamics (MD) simulations of SOD1 wild-type and variants A4V, D90A, H46R, and I113T, which account for approximately half of all ALS-SOD1 cases in the United States, Europe, Japan, and United Kingdom, respectively. 233 missense mutations in SOD1 protein were compiled from the databases and literature consulted. The predictive analyses pointed to an elevated rate of deleterious and destabilizing predictions for the analyzed variants, indicating their harmful effects. The ConSurf analysis suggested that mutations in SOD1 mainly affect conserved and possibly functionally essential amino acids. The MD analyses pointed to flexibility and essential dynamics alterations at the electrostatic and metal-binding loops of variants A4V, D90A, H46R, and I113T that could lead to aberrant interactions triggering toxic protein aggregation. These alterations may have harmful implications for SOD1 and explain their association with ALS. Understanding the effects of SOD1 mutations on protein structure and function facilitates the design of further experiments and provides relevant information on the molecular mechanism of pathology, which may contribute to improvements in existing treatments for ALS.

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Section: Introductionmentioning

confidence: 99%

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

2021

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“…The antioxidant effect of SOD1 can also provide protection for cancer cells or other dysfunctional cells. Mutations of the SOD1 gene have been linked to numerous human diseases and cancers, such as and Down syndrome and familial amyotrophic lateral sclerosis (ALS), Indeed 20% of ALS cases are associated with mutations in SOD1 (Brasil et al, 2019), Somwar et al (2011) reported that SOD1 was overexpressed in lung adenocarcinomas when compared with the normal lung tissue, while Glasauer et al (2014) found that inhibition of SOD1 by the small molecule ATN-224 induced NSCLC cell death. SOD1 also acts as a metabolic focal point, integrating O 2 , nutrients, and reactive oxygen species (ROS) to direct energy metabolism (Tsang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

Liu

et al. 2020

Front. Cell Dev. Biol.

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Superoxide dismutase 1(SOD1) is a major antioxidant with oncogenic effects in many human cancers. Although SOD1 is overexpressed in various cancers, the clinical significance and functions of SOD1 in non-small cell lung cancer (NSCLC), particularly the epigenetic regulation of SOD1 in NSCLC carcinogenesis and progression have been less well investigated. In this study, we found that SOD1 expression was upregulated in NSCLC cell lines and tissues. Further, elevated SOD1 expression could promote NSCLC cell proliferation, invasion and migration. While inhibition of SOD1 expression induced NSCLC G1-phase cell cycle arrest and promoted apoptosis. In addition, miR-409-3p could repress SOD1 expression and significantly counteract its oncogenic activities. Bioinformatics analysis indicated that SET domain bifurcated histone lysine methyltransferase1 (SETDB1) was involved in the epigenetic regulation of miR-409-3p and SOD1 expression and functions in NSCLC cells. Identification of this miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop may provide new insights into further understanding of NSCLC tumorigenesis and progression. Additionally, our results incicate that SOD1 may be a potential new therapeutic target for NSCLC treatment.

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“…Taking advantage of distinct electrophoretic mobilities of wild-type and mutant SOD1 proteins (G85R and L126Z), furthermore, wild-type human SOD1 was found to accumulate as detergent-insoluble aggregates with the mutant proteins in transgenic mice [ 29 , 31 , 33 , 34 ], while the interactions in the aggregates would not be simply a co-assembly of mutant and wild-type proteins [ 33 ]. A mechanism of disease-accelerating effects of wild-type SOD1 remains unclear, but heteromeric interactions between wild-type and mutant SOD1 appear to aggravate the aggregation and toxicity in cultured cell models [ 36 ] and have correlation with the disease severity [ 37 ]. It should be also noted that, in some studies, overexpression of wild-type human SOD1 did not affect the onset or duration of disease in mice expressing G85R-mutant human SOD1 [ 5 ] or G86R-mutant murine SOD1 [ 38 ].…”

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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Characterization of the activity, aggregation, and toxicity of heterodimers of WT and ALS-associated mutant Sod1

Cited by 47 publications

References 54 publications

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

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

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