Abstract
Amyotrophic lateral sclerosis (ALS), a complicated neurodegenerative disorder affected by hereditary and environmental variables, is a condition. In this study, the genetic makeup of ALS is investigated, with a focus on the SOD1 gene’s single-nucleotide polymorphisms (SNPs) and their ability to affect disease risk. Eleven high-risk missense variations that may impair the functionality of the SOD1 protein were discovered after a thorough examination of SNPs in the SOD1 gene. These mutations were chosen using a variety of prediction approaches, highlighting their importance in the aetiology of ALS. Notably, it was discovered that the stability of the SOD1 wild-type protein structure was compromised by the G38R and G42D SOD1 variants. Additionally, Edaravone, a possible ALS medication, showed a greater affinity for binding mutant SOD1 structures, pointing to potential personalised treatment possibilities. The high-risk SNPs discovered in this investigation seem to have functional effects, especially on the stability of proteins and their interactions with other molecules. This study clarifies the complex genetics of ALS and offers insights into how these genetic variations may affect the effectiveness of therapeutic interventions, particularly in the context of edaravone. In this study advances our knowledge of the genetic mechanisms causing ALS vulnerability and prospective therapeutic strategies. Future studies are necessary to confirm these results and close the gap between individualised clinical applications and improved ALS care.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated or analysed during this study are included in this published article.
Abbreviations
- ALS:
-
Amyotrophic lateral sclerosis
- ASA:
-
Accessible surface area
- cSNP:
-
Coding single nucleotide polymorphism
- GWAS:
-
Genome-wide association studies
- NGS:
-
Next generation sequencing
- nsSNPs:
-
Non-synonymous single nucleotide polymorphism
- nsSNVs:
-
Non-synonymous/missense single nucleotide variations
- PDB:
-
Protein data bank
- PSEC:
-
Position specific evolutionary conservation
- QMEAN:
-
Qualitative model energy analysis
- RSA:
-
Relative surface accessibility
- SA:
-
Surface area
- SAAFEC-SEQ:
-
Sequence-based stabilisation analysis of amino acid change
- SIFT:
-
Sorting intolerant from tolerant
- SNAP:
-
Screening for non-acceptable polymorphism
- SNPs:
-
Single nucleotide polymorphisms
- SOD1:
-
Superoxide dismutase 1
- STRING:
-
Search tool for the retrieval of interacting genes/proteins
References
Apte M, Kumar A (2023) Correlation of mutated gene and signalling pathways in ASD. IBRO Neurosci Rep. https://doi.org/10.1016/j.ibneur.2023.03.011
Bamshad C, Najafi-Ghalehlou N, Pourmohammadi-Bejarpasi Z, Tomita K, Kuwahara Y, Sato T et al (2022) Mitochondria: how eminent in ageing and neurodegenerative disorders? Hum Cell 36(1):41–61. https://doi.org/10.1007/s13577-022-00833-y
Berdyński M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S et al (2022) SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci Rep. https://doi.org/10.1038/s41598-021-03891-8
Besterman AD, Althoff T, Elfferich P, Gutierrez-Mejia I, Sadik J, Bernstein JA et al (2021) Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity. PLoS Genet 17(7):e1009651. https://doi.org/10.1371/journal.pgen.1009651
Bonifacino T, Zerbo RA, Balbi M, Torazza C, Frumento G, Fedele E et al (2021) Nearly 30 years of animal models to study amyotrophic lateral sclerosis: a historical overview and future perspectives. Int J Mol Sci 22(22):12236. https://doi.org/10.3390/ijms222212236
Candelise N, Salvatori I, Scaricamazza S, Nesci V, Zenuni H, Ferri A et al (2022) Mechanistic insights of mitochondrial dysfunction in amyotrophic lateral sclerosis: an update on a lasting relationship. Metabolites 12(3):233. https://doi.org/10.3390/metabo12030233
Chaudhary R, Agarwal V, Rehman M, Kaushik AS, Mishra V (2022) Genetic architecture of motor neuron diseases. J Neurol Sci 434(120099):120099. https://doi.org/10.1016/j.jns.2021.120099
Dang X, Zhang L, Franco A, Dorn GW II (2023) Activating mitofusins interrupts mitochondrial degeneration and delays disease progression in SOD1 mutant amyotrophic lateral sclerosis. Hum Mol Genet 32(7):1208–1222. https://doi.org/10.1093/hmg/ddac287
Daud S, Yousafzai A (2021) Study on amyotrophic lateral sclerosis: a disease of motor neuron in Pakistan. International Journal of Pathology 19(3):155–164
Deneault E, Chaineau M, Nicouleau M, Castellanos Montiel MJ, Franco Flores AK, Haghi G et al (2022) A streamlined CRISPR workflow to introduce mutations and generate isogenic iPSCs for modeling amyotrophic lateral sclerosis. Methods 203:297–310. https://doi.org/10.1016/j.ymeth.2021.09.002
Falahi S, Karaji AG, Koohyanizadeh F, Rezaiemanesh A, Salari F (2021) A comprehensive in Silico analysis of the functional and structural impact of single nucleotide polymorphisms (SNPs) in the human IL-33 gene. Comput Biol Chem 94(107560):107560. https://doi.org/10.1016/j.compbiolchem.2021.107560
Frlan R (2022) An evolutionary conservation and druggability analysis of enzymes belonging to the bacterial shikimate pathway. Antibiotics (basel) 11(5):675. https://doi.org/10.3390/antibiotics11050675
Gagliardi D, Ripellino P, Meneri M, Del Bo R, Antognozzi S, Comi GP et al (2023) Clinical and molecular features of patients with amyotrophic lateral sclerosis and SOD1 mutations: a monocentric study. Front Neurol 14:1169689. https://doi.org/10.3389/fneur.2023.1169689
Gao AY (2020) Investigating the loss of sodium/proton exchanger isoform 6 (nhe6) function in christianson syndrome. McGill University (Canada) ProQuest Dissertations Publishing, 2020. p 29274264
Goutman SA, Savelieff MG, Jang D-G, Hur J, Feldman EL (2023) The amyotrophic lateral sclerosis exposome: recent advances and future directions. Nat Rev Neurol 19(10):617–634. https://doi.org/10.1038/s41582-023-00867-2
Imran FS, Al-Thuwaini TM, Al-Shuhaib MBS, Lepretre F (2021) A novel missense single nucleotide polymorphism in the GREM1 gene is highly associated with higher reproductive traits in awassi sheep. Biochem Genet 59(2):422–436. https://doi.org/10.1007/s10528-020-10006-x
Jankovic M, Novakovic I, Gamil Anwar Dawod P, Gamil Anwar Dawod A, Drinic A, Abdel Motaleb FI et al (2021) Current concepts on genetic aspects of mitochondrial dysfunction in amyotrophic Lateral Sclerosis. Int J Mol Sci 22(18):9832. https://doi.org/10.3390/ijms22189832
Krokidis MG, Exarchos TP, Vlamos P (2022) Gene expression profiling and bioinformatics analysis in neurodegenerative diseases. Handbook of computational neurodegeneration. Springer International Publishing, Cham
Kumar M, Tyagi N, Faruq M (2023) The molecular mechanisms of spinocerebellar ataxias for DNA repeat expansion in disease. Emerg Topics Life Sci. https://doi.org/10.1042/ETLS20230013
Li B, Mendenhall J, Capra JA, Meiler J (2021) A multitask deep-learning method for predicting membrane associations and secondary structures of proteins. J Proteome Res 20(8):4089–4100. https://doi.org/10.1021/acs.jproteome.1c00410
Lünemann JD, Malhotra S, Shinohara ML, Montalban X, Comabella M (2021) Targeting inflammasomes to treat neurological diseases. Ann Neurol 90(2):177–188. https://doi.org/10.1002/ana.26158
Mathioudakis L, Dimovasili C, Bourbouli M, Latsoudis H, Kokosali E, Gouna G (2023) Study of Alzheimer’s disease-and frontotemporal dementia-associated genes in the Cretan Aging Cohort. Neurobiol Aging 123:111–128
Maung MT, Carlson A, Olea-Flores M, Elkhadragy L, Schachtschneider KM, Navarro-Tito N et al (2021) The molecular and cellular basis of copper dysregulation and its relationship with human pathologies. FASEB J. https://doi.org/10.1096/fj.202100273rr
McDonough SI (2022) From calcium channels to new therapeutics. Voltage-gated calcium channels. Springer International Publishing, Cham, pp 687–706
Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ (2023) Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov 22(3):185–212. https://doi.org/10.1038/s41573-022-00612-2
Meijboom KE, Brown RH (2022) Approaches to gene modulation therapy for ALS. Neurotherapeutics 19(4):1159–1179. https://doi.org/10.1007/s13311-022-01285-w
Oroian BA, Ciobica A, Timofte D, Stefanescu C, Serban IL (2021) New metabolic, digestive, and oxidative stress-related manifestations associated with posttraumatic stress disorder. Oxid Med Cell Longev 2021:1–18. https://doi.org/10.1155/2021/5599265
Pan S, Kang H, Liu X, Lin S, Yuan N, Zhang Z et al (2023) Brain Catalog: a comprehensive resource for the genetic landscape of brain-related traits. Nucleic Acids Res 51(D1):D835–D844. https://doi.org/10.1093/nar/gkac895
Park SW, Lee BH, Song SH, Kim MK (2023) Revisiting the Ramachandran plot based on statistical analysis of static and dynamic characteristics of protein structures. J Struct Biol 215(1):107939. https://doi.org/10.1016/j.jsb.2023.107939
Rafaee A, Kashani-Amin E, Meybodi AM, Ebrahim-Habibi A, Sabbaghian M (2022) Structural modeling of human AKAP3 protein and in silico analysis of single nucleotide polymorphisms associated with sperm motility. Sci Rep. https://doi.org/10.1038/s41598-022-07513-9
Rahman MM, Islam MR, Alam Tumpa MA, Shohag S, Khan Shuvo S, Ferdous J et al (2023) Insights into the promising prospect of medicinal chemistry studies against neurodegenerative disorders. Chem Biol Interact 373:110375. https://doi.org/10.1016/j.cbi.2023.110375
Roberts B, Theunissen F, Mastaglia FL, Akkari PA, Flynn LL (2022) Synucleinopathy in amyotrophic lateral sclerosis: a potential avenue for antisense therapeutics? Int J Mol Sci 23(16):9364. https://doi.org/10.3390/ijms23169364
Rozario LT, Sharker T, Nila TA (2021) In silico analysis of deleterious SNPs of human MTUS1 gene and their impacts on subsequent protein structure and function. PLoS ONE 16(6):e0252932. https://doi.org/10.1371/journal.pone.0252932
Ruffo P, Strafella C, Cascella R, Caputo V, Conforti FL, Andò S et al (2021) Deregulation of ncRNA in neurodegenerative disease: focus on circRNA, lncRNA and miRNA in amyotrophic lateral sclerosis. Front Genet. https://doi.org/10.3389/fgene.2021.784996
Ruffo P, Perrone B, Conforti FL (2022) SOD-1 variants in amyotrophic lateral sclerosis: Systematic re-evaluation according to ACMG-AMP guidelines. Genes (basel) 13(3):537. https://doi.org/10.3390/genes13030537
Shinwari K, Rehman HM, Xiao N, Guojun L, Khan MA, Bolkov MA et al (2023) Novel high-risk missense mutations identification in FAT4 gene causing Hennekam syndrome and Van Maldergem syndrome 2 through molecular dynamics simulation. Inform Med Unlocked 37(101160):101160. https://doi.org/10.1016/j.imu.2023.101160
Sivaramakrishnan V, Kumar A (2022) Structural systems biology approach delineate the functional implications of SNPs in exon junction complex interaction network. J Biomol Struct Dyn 41(21):11969–11986. https://doi.org/10.1080/07391102.2022.2164355
Stitou M, Toufik H, Bouachrine M, Lamchouri F (2021) Quantitative structure–activity relationships analysis, homology modeling, docking and molecular dynamics studies of triterpenoid saponins as Kirsten rat sarcoma inhibitors. J Biomol Struct Dyn 39(1):152–170. https://doi.org/10.1080/07391102.2019.1707122
Tasca G, Lattante S, Marangi G, Conte A, Bernardo D, Bisogni G et al (2020) SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum. Eur J Neurol 27(7):1304–1309. https://doi.org/10.1111/ene.14246
Tzeplaeff L, Wilfling S, Requardt MV, Herdick M (2023) Current state and future directions in the therapy of ALS. Cells 12(11):1523
Ullah S, Khan SU, Khan A, Junaid M, Rafiq H, Htar TT et al (2022) Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening. Mol Divers 26(3):1399–1409. https://doi.org/10.1007/s11030-021-10263-x
Vora D, Kapadia H, Dinesh S, Sharma S, Manjegowda DS (2023) Gymnema sylvestre as a potential therapeutic agent for PCOS: insights from mRNA differential gene expression and molecular docking analysis. Futur J Pharm Sci. https://doi.org/10.1186/s43094-023-00529-6
Wanarase SR, Chavan SV, Sharma S, Susha (2023) Evaluation of SNPs from human IGFBP6 associated with gene expression: an in-silico study. J Biomol Struct Dyn 41(23):13937–13949. https://doi.org/10.1080/07391102.2023.2192793
Wang JC, Ramaswami G, Geschwind DH (2021) Gene co-expression network analysis in human spinal cord highlights mechanisms underlying amyotrophic lateral sclerosis susceptibility. Sci Rep. https://doi.org/10.1038/s41598-021-85061-4
Wei Q, Zhou Q, Chen Y, Ou R, Cao B, Xu Y et al (2017) Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review. Sci Rep. https://doi.org/10.1038/srep44606
Wei T, Guo Z, Wang Z, Li X, Zheng Y, Hou H et al (2022) Exploring the causal relationship between dietary macronutrients and neurodegenerative diseases: a bi-directional two-sample Mendelian randomization study. Ageing Neur Dis 2(3):14. https://doi.org/10.20517/and.2022.12
Zaji HD, Seyedalipour B, Hanun HM, Baziyar P, Hosseinkhani S, Akhlaghi M (2023) Computational insight into in silico analysis and molecular dynamics simulation of the dimer interface residues of ALS-linked hSOD1 forms in apo/holo states: a combined experimental and bioinformatic perspective. 3 Biotech. https://doi.org/10.1007/s13205-023-03514-1
Zhou W, Xu R (2023) Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis. Front Neurosci 17:1189470. https://doi.org/10.3389/fnins.2023.1189470
Acknowledgements
We thank BioNome, Bangalore (www.bionome.in/) for providing insight in bioinformatics analysis and scientific article writing.
Funding
The present study is funded by the Department of Scientific Research and Education, BioNome (Funding ID: DSRE/BNM/SR/2023/A0115).
Author information
Authors and Affiliations
Contributions
All authors participated in the analysis, writing, reviewing, and editing of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
Declared none.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Bhor, S., Tonny, S.H., Dinesh, S. et al. Computational screening of damaging nsSNPs in human SOD1 genes associated with amyotrophic lateral sclerosis identifies destabilising effects of G38R and G42D mutations through in silico evaluation. In Silico Pharmacol. 12, 20 (2024). https://doi.org/10.1007/s40203-024-00191-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s40203-024-00191-7