Molecular mechanism of oxidation-induced TDP-43 RRM1 aggregation and loss of function

Cysteine oxidation of the two RNA recognition motifs (RRM1 and RRM2) of TDP-43, a multi-domain protein involved in neurodegenerative diseases, results in loss of function and accumulation of insoluble aggregates under both in vitro and in vivo conditions. However, the molecular mechanisms linking cysteine oxidation to protein aggregation and functional aberration remain unknown. We report that oxidation of cysteines in RRM1, but not in other domains, induced conformational changes which subsequently resulted in protein aggregation and loss of nucleic acid-binding activity. Thus, oxidation-induced conformational change of RRM1 plays a key role in TDP-43 aggregation and disease progression. Structured summary of protein interactions: RRM2 and RRM2 bind by molecular sieving (View Interaction: 1, 2, 3, 4) RRM1 and RRM1 bind by comigration in sds page (View Interaction: 1, 2, 3) RRM1 and RRM1 bind by classical fluorescence spectroscopy (View interaction) RRM2 and RRM2 bind by molecular sieving (View Interaction: 1, 2).