Title: Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking.

Authors: Cohen, Todd J; Hwang, Andrew W; Unger, Travis; Trojanowski, John Q; Lee, Virginia M Y

Published In EMBO J, (2012 Mar 7)

Abstract: TDP-43 is the major disease protein in ubiquitin-positive inclusions of amyotrophic lateral sclerosis and frontotemporal lobar degeneration (FTLD) characterized by TDP-43 pathology (FTLD-TDP). Accumulation of insoluble TDP-43 aggregates could impair normal TDP-43 functions and initiate disease progression. Thus, it is critical to define the signalling mechanisms regulating TDP-43 since this could open up new avenues for therapeutic interventions. Here, we have identified a redox-mediated signalling mechanism directly regulating TDP-43. Using in vitro and cell-based studies, we demonstrate that oxidative stress promotes TDP-43 cross-linking via cysteine oxidation and disulphide bond formation leading to decreased TDP-43 solubility. Biochemical analysis identified several cysteine residues located within and adjacent to the second RNA-recognition motif that contribute to both intra- and inter-molecular interactions, supporting TDP-43 as a target of redox signalling. Moreover, increased levels of cross-linked TDP-43 species are found in FTLD-TDP brains, indicating that aberrant TDP-43 cross-linking is a prominent pathological feature of this disease. Thus, TDP-43 is dynamically regulated by a redox regulatory switch that links oxidative stress to the modulation of TDP-43 and its downstream targets.

PubMed ID: 22193716

MeSH Terms: Amino Acid Sequence; Brain/pathology; Cell Line; Cysteine/metabolism*; DNA-Binding Proteins/metabolism*; Disulfides/metabolism*; Frontotemporal Lobar Degeneration/pathology; Humans; Molecular Sequence Data; Oxidation-Reduction; Oxidative Stress*; Signal Transduction*