GADD34 ENHANCES OXIDATIVE STRESS-INDUCED TDP-43 PHOSPHORYLATIONS LINKED TO NEURODEGENERATIVE DISEASE

Abstract

TAR DNA BINDING PROTEIN 43 (TDP-43) IS DEPOSITED INTO HIGHLY PHOSPHORYLATED AGGREGATES IN POST-MORTEM BRAINS OF PATIENTS SUFFERING FROM A WIDE SPECTRUM OF NEURODEGENERATIVE DISEASES. THOUGH THE CAUSE OF PHOSPHORYLATION IS UNKNOWN, ITS ABSENCE IN NORMAL TISSUES MAKES TDP-43 PHOSPHORYLATION A ROBUST BIOMARKER FOR TDP-43 PROTEINOPATHIES. A PROTEOMIC SCREEN FOR GADD34 (GROWTH ARREST AND DNA DAMAGE-INDUCIBLE PROTEIN)-INTERACTING PROTEINS IDENTIFIED TDP-43 AS A NOVEL GADD34 BINDER. GADD34 REGULATES PROTEIN PHOSPHATASE 1 TO DEPHOSPHORYLATE TRANSLATION INITIATION FACTOR, EIF2A, REGULATING PROTEIN SYNTHESIS AND PATHWAYS WHICH IMPACT CELL SURVIVAL. GADD34 AND TDP-43 ASSOCIATION WAS INCREASED BY OXIDATIVE STRESS INDUCED BY ARSENITE, WHICH RELIED ON OXIDATIVE MODIFICATION OF TDP-43?S CYSTEINES. STRIKINGLY, CHRONIC OXIDATIVE STRESS BY ARSENITE ALSO REPRODUCED PATHOLOGICAL TDP-43 PHOSPHORYLATED AGGREGATES WHICH WERE SIGNIFICANTLY DIMINISHED IN GADD34 KNOCKOUT CELLS. THIS MAY ARISE FROM DEFICIENT GAD