Academic Journal
The Ile35 Residue of the ALS-Associated Mutant SOD1 Plays a Crucial Role in the Intracellular Aggregation of the Molecule.
| Τίτλος: | The Ile35 Residue of the ALS-Associated Mutant SOD1 Plays a Crucial Role in the Intracellular Aggregation of the Molecule. |
|---|---|
| Συγγραφείς: | Asai Y; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan., Yano K; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan., Higashino T; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan., Yoshihara D; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan.; Labolatory of Biochemistry, School of Pharmacy, Hyogo Medical University, Kobe, Hyogo, 650-8530, Japan., Sakiyama H; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan.; Faculty of Nutrition, Department of Food and Nutrition, Senri Kinran University, Suita, Osaka, 565-0873, Japan., Eguchi H; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan., Fukushima K; Department of Chemistry, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, 663-8501, Japan., Suzuki K; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan., Fujiwara N; Department of Biochemistry, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan. noriko-f@hyo-med.ac.jp. |
| Πηγή: | Molecular neurobiology [Mol Neurobiol] 2025 Feb; Vol. 62 (2), pp. 2023-2038. Date of Electronic Publication: 2024 Jul 26. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Clifton, NJ : Humana Press, c1987- |
| Ιατρικοί όροι (MeSH): | Amyotrophic Lateral Sclerosis*/genetics , Amyotrophic Lateral Sclerosis*/enzymology , Amyotrophic Lateral Sclerosis*/pathology , Mutation*/genetics , Superoxide Dismutase*/genetics , Superoxide Dismutase*/metabolism , Superoxide Dismutase*/chemistry , Intracellular Space*/metabolism , Mutant Proteins*/metabolism , Mutant Proteins*/chemistry , Protein Aggregates* , Protein Aggregation, Pathological*, Green Fluorescent Proteins/metabolism ; Superoxide Dismutase-1 ; Humans ; Animals |
| Περίληψη: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unknown pathogenesis. It has been reported that mutations in the gene for Cu/Zn superoxide dismutase (SOD1) cause familial ALS. Mutant SOD1 undergoes aggregation and forms amyloid more easily, and SOD1-immunopositive inclusions have been observed in the spinal cords of ALS patients. Because of this, SOD1 aggregation is thought to be related to the pathogenesis of ALS. Some core regions of amyloid have been identified, but the issue of whether these regions form aggregates in living cells remains unclear, and the mechanism responsible for intracellular SOD1 aggregation also remains unclear. The findings reported in this study indicate that the aggregation of the ALS-linked mutant SOD1-EGFP was significantly enhanced when the BioID2 gene was fused to the N-terminus of the mutant SOD1-EGFP plasmid for cellular expression. Expression of a series of BioID2-(C-terminal deletion peptides of SOD1)-EGFP permitted us to identify 1-35 as a minimal N-terminal sequence and Ile35 as an essential amino acid residue that contributes to the intracellular aggregation of SOD1. The findings also showed that an additional substitution of Ile35 with Ser into the ALS mutant SOD1 resulted in the significant suppression of aggregate formation. The fact that no Ile35 mutations have been reported to date in ALS patients indicates that all ALS mutant SOD1s contain Ile35. Taken together, we propose that Ile35 plays a pivotal role in the aggregation of the ALS-linked SOD1 and that this study will contribute to our understanding of the mechanism responsible for SOD1 aggregation. (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) |
| Competing Interests: | Declarations. Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests. |
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| Grant Information: | 22K11870 Japan Society for the Promotion of Science |
| Contributed Indexing: | Keywords: Aggresomes; Amyotrophic lateral sclerosis (ALS); Cu/Zn superoxide dismutase (SOD1); Intracellular aggregation; Neurodegeneration |
| Substance Nomenclature: | EC 1.15.1.1 (Superoxide Dismutase-1) 0 (SOD1 protein, human) 0 (Protein Aggregates) EC 1.15.1.1 (Superoxide Dismutase) 147336-22-9 (Green Fluorescent Proteins) 0 (Mutant Proteins) |
| Entry Date(s): | Date Created: 20240726 Date Completed: 20250423 Latest Revision: 20250514 |
| Update Code: | 20260130 |
| DOI: | 10.1007/s12035-024-04369-0 |
| PMID: | 39060907 |
| Βάση Δεδομένων: | MEDLINE |
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