Molecular Modulation of the Crosstalk Between TDP-43 and SOD1

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Glycation of superoxide dismutase 1 (SOD1) influences phosphorylated TAR DNA-binding protein 43 (TDP-43) levels, a key factor in amyotrophic lateral sclerosis (ALS).
• The interplay between SOD1 and TDP-43 is crucial in understanding ALS pathogenesis.

Purpose of the Study:

• To investigate the interaction between TDP-43 and SOD1.
• To assess the impact of methylglyoxal (MGO)-induced glycation and the G93A SOD1 mutation on this interaction in H4 cells.

Main Methods:

• Utilized H4 cell lines expressing wild-type (WT) and G93A mutant SOD1.
• Exposed cells to methylglyoxal (MGO) to induce glycation.
• Analyzed SOD1 activity, TDP-43 phosphorylation, protein interactions, and inclusion formation.
• Investigated the effect of cyclosporin A treatment.

Main Results:

• MGO reduced SOD1 activity and TDP-43 phosphorylation in WT SOD1 cells, but not in G93A SOD1 cells.
• Both WT and mutant SOD1 interacted with TDP-43 in the nucleus and cytosol, with increased cytosolic interaction for G93A SOD1.
• MGO induced TDP-43-SOD1 cytosolic inclusions in WT cells, independent of stress granules.
• Cyclosporin A treatment reduced TDP-43-SOD1 inclusions and cytosolic interactions.

Conclusions:

• SOD1 damage, via glycation or mutation, impacts TDP-43 phosphorylation and promotes its cytosolic mislocalization and aggregation.
• These findings offer new insights into proteinopathy in ALS.
• The phosphatase calcineurin may play a role in regulating TDP-43-SOD1 interactions and aggregation.