Biomolecules (Aug 2019)

Thimet Oligopeptidase (EC 3.4.24.15) Key Functions Suggested by Knockout Mice Phenotype Characterization

  • Nilton B. dos Santos,
  • Roseane D. Franco,
  • Rosana Camarini,
  • Carolina D. Munhoz,
  • Rosangela A. S. Eichler,
  • Mayara C. F. Gewehr,
  • Patricia Reckziegel,
  • Ricardo P. Llanos,
  • Camila S. Dale,
  • Victoria R. O. da Silva,
  • Vanessa F. Borges,
  • Braulio H. F. Lima,
  • Fernando Q. Cunha,
  • Bruna Visniauskas,
  • Jair R. Chagas,
  • Sergio Tufik,
  • Fernanda F. Peres,
  • Vanessa C. Abilio,
  • Jorge C. Florio,
  • Leo K. Iwai,
  • Vanessa Rioli,
  • Benedito C. Presoto,
  • Alessander O. Guimaraes,
  • Joao B. Pesquero,
  • Michael Bader,
  • Leandro M. Castro,
  • Emer S. Ferro

DOI
https://doi.org/10.3390/biom9080382
Journal volume & issue
Vol. 9, no. 8
p. 382

Abstract

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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.

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