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
Affiliations
- Nilton B. dos Santos
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Roseane D. Franco
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Rosana Camarini
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Carolina D. Munhoz
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Rosangela A. S. Eichler
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Mayara C. F. Gewehr
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Patricia Reckziegel
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Ricardo P. Llanos
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Camila S. Dale
- Department of Anatomy, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Victoria R. O. da Silva
- Department of Anatomy, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Vanessa F. Borges
- Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
- Braulio H. F. Lima
- Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
- Fernando Q. Cunha
- Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
- Bruna Visniauskas
- Department of Psychobiology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, Brazil
- Jair R. Chagas
- Department of Psychobiology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, Brazil
- Sergio Tufik
- Department of Psychobiology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, Brazil
- Fernanda F. Peres
- Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo, SP 04023-062, Brazil
- Vanessa C. Abilio
- Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo, SP 04023-062, Brazil
- Jorge C. Florio
- Department of Pathology, Veterinarian Medical School, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- Leo K. Iwai
- Special Laboratory of Applied Toxinology (LETA), Center of Toxins, Immune Response and Cell Signaling (CETICS), Butantan Institute, São Paulo 05503-900, Brazil
- Vanessa Rioli
- Special Laboratory of Applied Toxinology (LETA), Center of Toxins, Immune Response and Cell Signaling (CETICS), Butantan Institute, São Paulo 05503-900, Brazil
- Benedito C. Presoto
- Pharmacology Laboratory, Butantan Institute, São Paulo 05503-900, Brazil
- Alessander O. Guimaraes
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo, SP 04023-062, Brazil
- Joao B. Pesquero
- Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo, SP 04023-062, Brazil
- Michael Bader
- Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin, Germany
- Leandro M. Castro
- Biosciences Institute, São Paulo State University (UNESP), São Vicente, SP 11330-900, Brazil
- Emer S. Ferro
- Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo, SP 05508-000, Brazil
- DOI
- https://doi.org/10.3390/biom9080382
- Journal volume & issue
-
Vol. 9,
no. 8
p. 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.
Keywords