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Does conserved domain SOD1 mutation has any role in ALS severity and therapeutic outcome?

ABSTRACT: BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative fatal disease that can affect the neurons of brain and spinal cord. ALS genetics has identified various genes to be associated with disease pathology. Oxidative stress induced bunina and lewy bodies formation can be regulated through the action of SOD1 protein. Hence, in the present study we aim to analyse the structural and functional annotation of various reported SOD1 variants throughout and their putative correlation with the location of mutation and degree of ALS severity by inferring the structural and functional alterations in different SOD1 variants. METHODS:We have retrieved around 69 SNPs of SOD1 gene from Genecards. Structural annotation of SOD1 variants were performed using SWISS Model, I-Mutant 2.0, Dynamut, ConSurf. Similarly, the functional annotation of same variants were done using SIFT, PHP-SNP, PolyPhen2, PROVEAN and RegulomeDB. Ramachandran plot was also obtained for six synonymous SNPs to compare the amino acid distribution of wild-type SOD1 (WT SOD1) protein. Frequency analysis, Chi square analysis, ANOVA and multiple regression analysis were performed to compare the structural and functional components among various groups. RESULTS AND CONCLUSION:Results showed the mutations in conserved domain of SOD1 protein are more deleterious and significantly distort the tertiary structure of protein by altering Gibb's free energy and entropy. Moreover, significant changes in SIFT, PHP-SNP, PolyPhen2, PROVEAN and RegulomeDB scores were also observed in mutations located in conserved domain of SOD1 protein. Multiple regression results were also suggesting the significant alterations in free energy and entropy for conserved domain mutations which were concordant with structural changes of SOD1 protein. Results of the study are suggesting the biological importance of location of mutation(s) which may derive the different disease phenotypes and must be dealt accordingly to provide precise therapy for ALS patients.

SUBMITTER: Pal S

PROVIDER: S-EPMC7547430 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Does conserved domain SOD1 mutation has any role in ALS severity and therapeutic outcome?

Pal Surinder S Tiwari Abha A Sharma Kaushal K Sharma Suresh Kumar SK

BMC neuroscience 20201009 1

<h4>Background</h4>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative fatal disease that can affect the neurons of brain and spinal cord. ALS genetics has identified various genes to be associated with disease pathology. Oxidative stress induced bunina and lewy bodies formation can be regulated through the action of SOD1 protein. Hence, in the present study we aim to analyse the structural and functional annotation of various reported SOD1 variants throughout and their putati ...[more]

PMID: 33036560

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Project description:While the death of motor neuron is a pathological hallmark of amyotrophic lateral sclerosis (ALS), defects in other cell types or organs may also actively contribute to ALS disease progression. ALS patients experience progressive skeletal muscle wasting that may not only exacerbate neuronal degeneration, but likely has a significant impact on bone function. In our previous published study, we have discovered severe bone loss in an ALS mouse model with overexpression of ALS-associated mutation SOD1G93A (G93A). Here we further provide a mechanistic understanding of the bone loss in ALS animal and cellular models. Combining mitochondrial fluorescent indicators and confocal live cell imaging, we discovered abnormalities in mitochondrial network and dynamics in primary osteocytes derived from the same ALS mouse model G93A. Those mitochondrial defects occur in ALS mice after the onset of neuromuscular symptoms, indicating that mitochondria in bone cells respond to muscle atrophy during ALS disease progression. To examine whether ALS mutation has a direct contribution to mitochondrial dysfunction independent of muscle atrophy, we evaluated mitochondrial morphology and motility in cultured osteocytes (MLO-Y4) with overexpression of mitochondrial targeted SOD1G93A. Compared with osteocytes overexpressing the wild type SOD1 as a control, the SOD1G93A osteocytes showed similar defects in mitochondrial network and dynamic as that of the primary osteocytes derived from the ALS mouse model. In addition, we further discovered that overexpression of SOD1G93A enhanced the expression level of dynamin-related protein 1 (Drp1), a key protein promoting mitochondrial fission activity, and reduced the expression level of optic atrophy protein 1 (OPA1), a key protein related to mitochondrial fusion. A specific mitochondrial fission inhibitor (Mdivi-1) partially reversed the effect of SOD1G93A on mitochondrial network and dynamics, indicating that SOD1G93A likely promotes mitochondrial fission, but suppresses the fusion activity. Our data provide the first evidence that mitochondria show abnormality in osteocytes derived from an ALS mouse model. The accumulation of mutant SOD1G93A protein inside mitochondria directly causes dysfunction in mitochondrial dynamics in cultured MLO-Y4 osteocytes. In addition, the ALS mutation SOD1G93A-mediated dysfunction in mitochondrial dynamics is associated with an enhanced apoptosis in osteocytes, which could be a potential mechanism underlying the bone loss during ALS progression.

Project description:"Prion-like propagation" has recently been proposed for disease spread in Cu/Zn superoxide dismutase 1 (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). Pathological SOD1 conformers are presumed to propagate via cell-to-cell transmission. In this model, the risk-based kinetics of neuronal cell loss over time appears to be represented by a sigmoidal function that reflects the kinetics of intercellular transmission. Here, we describe an alternative view of prion-like propagation in SOD1-linked ALS - its relation to disease prognosis under the protective-aggregation hypothesis. Nucleation-dependent polymerization has been widely accepted as the molecular mechanism of prion propagation. If toxic species of misfolded SOD1, as soluble oligomers, are formed as on-pathway intermediates of nucleation-dependent polymerization, further fibril extension via sequential addition of monomeric mutant SOD1 would be protective against neurodegeneration. This is because the concentration of unfolded mutant SOD1 monomers, which serve as precursor of nucleation and toxic species of mutant SOD1, would decline in proportion to the extent of aggregation. The nucleation process requires that native conformers exist in an unfolded state that may result from escaping the cellular protein quality control machinery. However, prion-like propagation-SOD1 aggregated form self-propagates by imposing its altered conformation on normal SOD1-appears to antagonize the protective role of aggregate growth. The cross-seeding reaction with normal SOD1 would lead to a failure to reduce the concentration of unfolded mutant SOD1 monomers, resulting in continuous nucleation and subsequent generation of toxic species, and influence disease prognosis. In this alternative view, the kinetics of neuronal loss appears to be represented by an exponential function, with decreasing risk reflecting the protective role of aggregate and the potential for cross-seeding reactions between mutant SOD1 and normal SOD1.

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Does conserved domain SOD1 mutation has any role in ALS severity and therapeutic outcome?

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Does conserved domain SOD1 mutation has any role in ALS severity and therapeutic outcome?

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