title: Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Cohen
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Hwang
authors.forename: Travis
authors.initials: T
authors.lastname: Unger
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D004220:Disulfides; D003545:Cysteine