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Thimet oligopeptidase (EC 3.4.24.15) key functions suggested by knockout mice phenotype characterization

Authors

  • N.B.D. Santos
  • R.D. Franco
  • R. Camarini
  • C.D. Munhoz
  • R.A.S. Eichler
  • M.C.F. Gewehr
  • P. Reckziegel
  • R.P. Llanos
  • C.S. Dale
  • V.R.O. da Silva
  • V.F. Borges
  • B.H.F. Lima
  • F.Q. Cunha
  • B. Visniauskas
  • J.R. Chagas
  • S. Tufik
  • F.F. Peres
  • V.C. Abilio
  • J.C. Florio
  • L.K. Iwai
  • V. Rioli
  • B.C. Presoto
  • A.O. Guimaraes
  • J.B. Pesquero
  • M. Bader
  • L.M. Castro
  • E.S. Ferro

Journal

  • Biomolecules

Citation

  • Biomolecules 9 (8): 382

Abstract

  • Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1(-/-)) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies per litter similar to C57BL/6 wild type mice (WT). In specific brain regions, THOP1(-/-) exhibit altered mRNA expression of proteasome beta5, serotonin 5HT2a receptor and dopamine D2 receptor, but not of neurolysin (NLN). Peptidomic analysis identifies differences in intracellular peptide ratios between THOP1(-/-) and WT mice, which may affect normal cellular functioning. In an experimental model of multiple sclerosis THOP1(-/-) mice present worse clinical behavior scores compared to WT mice, corroborating its possible involvement in neurodegenerative diseases. THOP1(-/-) mice also exhibit better survival and improved behavior in a sepsis model, but also a greater peripheral pain sensitivity measured in the hot plate test after bradykinin administration in the paw. THOP1(-/-) mice show depressive-like behavior, as well as attention and memory retention deficits. Altogether, these results reveal a role of THOP1 on specific behaviors, immune-stimulated neurodegeneration, and infection-induced inflammation.


DOI

doi:10.3390/biom9080382