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Mutations in the gene encoding human superoxide dismutase 1 (hSOD1) were among the first to be proposed in line with the protein aggregation theory for ALS disease. This study aimed to characterize the (G41D) mutation\/charge effects on the biochemical and biophysical properties of the SOD1 structure through computational and experimental methods. The computed average values of RMSD, RMSF, and Rg demonstrate that mutation results in a loss of conformational stability, increased flexibility, and greater compactness, all supporting the observed aggregation. The G41D mutant revealed distinct changes in \u03b2-sheet content compared to WT-SOD1 under amyloidogenic conditions, as confirmed by FTIR spectroscopy. Furthermore, the formation of amyloid\/amorphous species was identified using ThT\/ANS fluorescence and confirmed by TEM analysis. Mutations that alter the net negative charge of the SOD1 protein are crucial in misfolding and shortening the lag phase in SOD1 aggregation. Our results provide supporting evidence that these charge alterations, alongside amyloid-inducing agents at near-physiological pH, significantly contribute to the formation of amyloid-like species. Therefore, studying the G41D mutation may provide valuable insights into the mechanisms of fALS-associated aggregate formation, which holds promise for the development of highly effective inhibitors in reducing aggregates and therapeutic potential.<\/jats:p>","DOI":"10.1038\/s41598-025-16910-9","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T21:58:59Z","timestamp":1756331939000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Uncovering the protein aggregation process through effect of G41D mutant SOD1 charge variation in ALS disease"],"prefix":"10.1038","volume":"15","author":[{"given":"Zainab Abdullah","family":"Waheed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6536-8250","authenticated-orcid":false,"given":"Abasalt Hosseinzadeh","family":"Colagar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bagher","family":"Seyedalipour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Payam","family":"Baziyar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"16910_CR1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","volume":"75","author":"F Chiti","year":"2006","unstructured":"Chiti, F. & Dobson, C. 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