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Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1.

TDP-43 (43-kDa TAR DNA-binding domain protein) is a major constituent of ubiquitin-positive cytoplasmic aggregates present in neurons of patients with fronto-temporal lobular dementia and amyotrophic lateral sclerosis (ALS). The pathologic significance of TDP-43 aggregation is not known; however, dominant mutations in TDP-43 cause a subset of ALS cases, suggesting that misfolding and/or altered trafficking of TDP-43 is relevant to the disease process. Here, we show that the presenilin-binding protein ubiquilin 1 (UBQLN) plays a role in TDP-43 aggregation. TDP-43 interacted with UBQLN both in yeast and in vitro, and the carboxyl-terminal ubiquitin-associated domain of UBQLN was both necessary and sufficient for binding to polyubiquitylated forms of TDP-43. Overexpression of UBQLN recruited TDP-43 to detergent-resistant cytoplasmic aggregates that colocalized with the autophagosomal marker, LC3. UBQLN-dependent aggregation required the UBQLN UBA domain, was mediated by non-overlapping regions of TDP-43, and was abrogated by a mutation in UBQLN previously linked to Alzheimer disease. Four ALS-associated alleles of TDP-43 also coaggregated with UBQLN, and the extent of aggregation correlated with in vitro UBQLN binding affinity. Our findings suggest that UBQLN is a polyubiquitin-TDP-43 cochaperone that mediates the autophagosomal delivery and/or proteasome targeting of TDP-43 aggregates.

Pubmed ID: 19112176


  • Kim SH
  • Shi Y
  • Hanson KA
  • Williams LM
  • Sakasai R
  • Bowler MJ
  • Tibbetts RS


The Journal of biological chemistry

Publication Data

March 20, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA124722

Mesh Terms

  • Alzheimer Disease
  • Amyotrophic Lateral Sclerosis
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • HeLa Cells
  • Humans
  • Microtubule-Associated Proteins
  • Molecular Chaperones
  • Mutation
  • Proteasome Endopeptidase Complex
  • Protein Folding
  • Protein Structure, Tertiary
  • Ubiquitination