Journal Article

DZNE-2026-00468

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.

Ribeiro, G. D. ; Queiroz, D. D. ; Monteiro-Neto, J. R. ; Gerhardt, E. ; de Souza, G. F. ; Albino, P. C. S. C. ; Paranhos, L. H. ; Outeiro, T. F.DZNE* ; Eleutherio, E. C. A.

2026
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: doi:10.3390/ijms27083409

Abstract: 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.

Keyword(s): Superoxide Dismutase-1: metabolism (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Humans (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Phosphorylation: drug effects (MeSH) ; Pyruvaldehyde: pharmacology (MeSH) ; Mutation (MeSH) ; Cytosol: metabolism (MeSH) ; Protein Binding (MeSH) ; Glycosylation (MeSH) ; SOD1 ; TDP-43 ; amyotrophic lateral sclerosis ; glycation ; proteinopathy ; Superoxide Dismutase-1 ; DNA-Binding Proteins ; TARDBP protein, human ; Pyruvaldehyde ; SOD1 protein, human

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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