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Redox signalling directly regulates TDP‐43 via cysteine oxidation and disulphide cross‐linking

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

Author Affiliations

  1. Todd J Cohen1,
  2. Andrew W Hwang1,
  3. Travis Unger1,
  4. John Q Trojanowski1 and
  5. Virginia M Y Lee*,1
  1. 1 Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
  1. *Corresponding author. Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3rd Floor, Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104‐4283, USA. Tel.: +1 215 662 6427; Fax: +1 215 349 5909; E-mail: vmylee{at}upenn.edu
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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.

  • Received August 22, 2011.
  • Accepted November 30, 2011.
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