Cytoplasmic TDP-43 impairs the activity of the ubiquitin-proteasome system.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE
    • Publication Information:
      Publication: Orlando Fl : Academic Press
      Original Publication: New York.
    • Subject Terms:
      Aging/*metabolism ; Cytoplasm/*metabolism ; DNA-Binding Proteins/*metabolism ; Motor Cortex/*metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Ubiquitin/*metabolism; Aging/pathology ; Animals ; Cell Line, Tumor ; Cytoplasm/pathology ; Humans ; Macaca fascicularis ; Mice ; Motor Cortex/pathology
    • Abstract:
      The cytoplasmic inclusions of nuclear TAR DNA-binding protein 43 (TDP-43) are a pathologic hallmark in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), and other neurological disorders. We reported that expressing mutant TDP-43(M337V) in rhesus monkeys can mimic the cytoplasmic mislocalization of mutant TDP-43 seen in patient brains. Here we investigated how cytoplasmic mutant TDP-43 mediates neuropathology. We found that C-terminal TDP-43 fragments are primarily localized in the cytoplasm and that the age-dependent elevated UBE2N promotes the accumulation of cytoplasmic C-terminal TDP-43 via K63 ubiquitination. Immunoprecipitation and mass spectrometry revealed that cytoplasmic mutant TDP-43 interacts with proteasome assembly proteins PSMG2 and PSD13, which might lead to the impairment of the proteasomal activity. Our findings suggest that cytoplasmic TDP-43 may participate in age-dependent accumulation of misfolded proteins in the brain by inhibiting the UPS activity.
      (Copyright © 2021. Published by Elsevier Inc.)
    • Contributed Indexing:
      Keywords: Aggregate; Non-human primate; TDP-43; UBE2N; Ubiquitin-proteasomal system
    • Accession Number:
      0 (DNA-Binding Proteins)
      0 (TARDBP protein, human)
      0 (Ubiquitin)
      EC 3.4.25.1 (Proteasome Endopeptidase Complex)
    • Publication Date:
      Date Created: 20210807 Date Completed: 20211221 Latest Revision: 20211221
    • Publication Date:
      20231215
    • Accession Number:
      10.1016/j.expneurol.2021.113833
    • Accession Number:
      34363810