title: Reducing TDP-43 aggregation does not prevent its cytotoxicity.
abstract: BACKGROUND
  TAR DNA-binding protein 43 (TDP-43) is a protein that is involved in the pathology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In patients with these neurodegenerative diseases, TDP-43 does not remain in its normal nuclear location, but instead forms insoluble aggregates in both the nucleus and cytoplasm of affected neurons.
  
  
  RESULTS
  We used high density peptide array analysis to identify regions in TDP-43 that are bound by TDP-43 itself and designed candidate peptides that might be able to reduce TDP-43 aggregation. We found that two of the synthetic peptides identified with this approach could effectively inhibit the formation of TDP-43 protein aggregates in a concentration-dependent manner in HeLa cells in which a mutated human TDP-43 gene was overexpressed. However, despite reducing aggregation, these peptides did not reduce or prevent cell death. Similar results were observed in HeLa cells treated with arsenite. Again we found reduced aggregation, in this case of wild type TDP-43, but no difference in cell death.
  
  
  CONCLUSIONS
  Our results suggest that TDP-43 aggregation is associated with the cell death process rather than being a direct cause.
authors.affiliation: Brain Research Center, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC V6T2B5, Canada. cynader@brain.ubc.ca.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: William
authors.initials: W
authors.lastname: Jia
authors.forename: Max S
authors.initials: MS
authors.lastname: Cynader
mesh_terms: D018053:Arsenites / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D009154:Mutation; D011485:Protein Binding
chemical_list: D018053:Arsenites; D004268:DNA-Binding Proteins; C015001:arsenite