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Structural and functional analysis of human SOD1 in amyotrophic lateral sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with familial inheritance (fALS) in 5% to 10% of cases; 25% of those are caused by mutations in the superoxide dismutase 1 (SOD1) protein. More than 100 mutations in the SOD1 gene have been associated with fALS, altering the geometry of the active site, protein folding and the interaction between monomers. We performed a functional analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in 124 fALS SOD1 mutants. Eleven different algorithms were used to estimate the functional impact of the replacement of one amino acid on protein structure: SNPs&GO, PolyPhen-2, SNAP, PMUT, Sift, PhD-SNP, nsSNPAnalyzer, TANGO, WALTZ, LIMBO and FoldX. For the structural analysis, theoretical models of 124 SNPs of SOD1 were created by comparative modeling using the MHOLline workflow, which includes Modeller and Procheck. Models were aligned with the native protein by the TM-align algorithm. A human-curated database was developed using the server side include in Java, JMOL. The results of this functional analysis indicate that the majority of the 124 natural mutants are harmful to the protein structure and thus corroborate the correlation between the reported mutations and fALS. In the structural analysis, all models showed conformational changes when compared to wild-type SOD1, and the degree of structural alignment varied between them. The SOD1 database converge structural and functional analyses of SOD1; it is a vast resource for the molecular analysis of amyotrophic lateral sclerosis, which allows the user to expand his knowledge on the molecular basis of the disease. The SOD1 database is available at http://bioinfogroup.com/database.

SUBMITTER: Moreira LG

PROVIDER: S-EPMC3846731 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Structural and functional analysis of human SOD1 in amyotrophic lateral sclerosis.

Moreira Lorenna Giannini Alves LG Pereira Livia Costa LC Drummond Priscila Ramalho PR De Mesquita Joelma Freire JF

PloS one 20131202 12

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with familial inheritance (fALS) in 5% to 10% of cases; 25% of those are caused by mutations in the superoxide dismutase 1 (SOD1) protein. More than 100 mutations in the SOD1 gene have been associated with fALS, altering the geometry of the active site, protein folding and the interaction between monomers. We performed a functional analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in 124 fALS SOD1 mutants. ...[more]

PMID: 24312616

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Project description:Innate neuroimmune dysfunction is a pathobiological feature of amyotrophic lateral sclerosis (ALS). However, links, if any, between disease and adaptive immunity are poorly understood. Thus, the role of T cell immunity in disease was investigated in human G93A superoxide dismutase 1 (SOD1) transgenic (Tg) mice and subsequently in ALS patients.Quantitative and qualitative immune deficits in lymphoid cell and T cell function were seen in G93A-SOD1 Tg mice. Spleens of Tg animals showed reductions in size, weight, lymphocyte numbers, and morphological deficits at terminal stages of disease compared to their wild-type (Wt) littermates. Spleen sizes and weights of pre-symptomatic Tg mice were unchanged, but deficits were readily seen in T cell proliferation coincident with increased annexin-V associated apoptosis and necrosis of lymphocytes. These lymphoid deficits paralleled failure of Copolymer-1 (COP-1) immunization to affect longevity. In addition, among CD4(+) T cells in ALS patients, levels of CD45RA(+) (naïve) T cells were diminished, while CD45RO(+) (memory) T cells were increased compared to age-matched caregivers. In attempts to correct mutant SOD1 associated immune deficits, we reconstituted SOD1 Tg mice with unfractionated naïve lymphocytes or anti-CD3 activated CD4(+)CD25(+) T regulatory cells (Treg) or CD4(+)CD25(-) T effector cells (Teff) from Wt donor mice. While naive lymphocytes failed to enhance survival, both polyclonal-activated Treg and Teff subsets delayed loss of motor function and extended survival; however, only Treg delayed neurological symptom onset, whereas Teff increased latency between disease onset and entry into late stage.A profound and progressive immunodeficiency is operative in G93A-SOD1 mice and is linked to T cell dysfunction and the failure to elicit COP-1 neuroprotective immune responses. In preliminary studies T cell deficits were also observed in human ALS. These findings, taken together, suggest caution in ascribing vaccination outcomes when these animal models of human ALS are used for study. Nonetheless, the abilities to improve neurological function and life expectancy in G93A-SOD1 Tg mice by reconstitution with activated T cells do provide opportunities for therapeutic intervention.

Dataset Information

Structural and functional analysis of human SOD1 in amyotrophic lateral sclerosis.

Publications

Structural and functional analysis of human SOD1 in amyotrophic lateral sclerosis.

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