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Molecular Modulation of the Crosstalk Between TDP-43 and SOD1

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2026 by the authors. Glycation of superoxide dismutase 1 (SOD1) has been shown to modulate the cytosolic levels of phosphorylated TAR DNA-binding protein 43 (TDP-43), a hallmark of amyotrophic lateral sclerosis (ALS) pathology. In this study, we investigated the interaction between TDP-43 and SOD1 and assessed how methylglyoxal (MGO)-induced glycation and the ALS-associated G93A SOD1 mutation affect this interplay in H4 cells. MGO exposure reduced SOD1 activity and TDP-43 phosphorylation in cells expressing WT SOD1, but not in those expressing G93A SOD1. Both WT and mutant SOD1 interacted with TDP-43 in the nucleus and cytosol; however, cytosolic interactions were more prevalent in G93A-expressing cells. Although MGO did not significantly alter the overall interaction between TDP-43 and WT SOD1, it induced cytosolic inclusion formation at 0.4 mM, a concentration associated with reduced cell viability. These inclusions did not colocalize with stress granules, indicating alternative aggregation pathways. Treatment with cyclosporin A, which inhibits the phosphatase calcineurin, decreased both TDP-43–WT SOD1 inclusions and cytosolic interactions between TDP-43 and G93A SOD1. Together, these findings suggest that SOD1 damage, induced by glycation or ALS-linked mutation, may affect TDP-43 phosphorylation status and promote its cytosolic mislocalization and aggregation, providing new insights into ALS-associated proteinopathy.

Publication metadata

Author(s): Ribeiro GD, Queiroz DD, Monteiro-Neto JR, Gerhardt E, de Souza GF, Albino PCSC, Paranhos LH, Outeiro TF, Eleutherio ECA

Publication type: Article

Publication status: Published

Journal: International Journal of Molecular Sciences

Year: 2026

Volume: 27

Issue: 8

Online publication date: 10/04/2026

Acceptance date: 07/04/2026

Date deposited: 12/05/2026

ISSN (print): 1661-6596

ISSN (electronic): 1422-0067

Publisher: MDPI

URL: https://doi.org/10.3390/ijms27083409

DOI: 10.3390/ijms27083409

Data Access Statement: The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

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