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

Autor: Santos NBD; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Franco RD; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Camarini R; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Munhoz CD; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Eichler RAS; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Gewehr MCF; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Reckziegel P; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil.; Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Llanos RP; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Dale CS; Department of Anatomy, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Silva VROD; Department of Anatomy, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Borges VF; Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil., Lima BHF; Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil., Cunha FQ; Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil., Visniauskas B; Department of Psychobiology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Chagas JR; Department of Psychobiology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Tufik S; Department of Psychobiology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Peres FF; Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Abilio VC; Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Florio JC; Department of Pathology, Veterinarian Medical School, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil., Iwai LK; Special Laboratory of Applied Toxinology (LETA), Center of Toxins, Immune Response and Cell Signaling (CETICS), Butantan Institute, São Paulo 05503-900, Brazil., Rioli V; Special Laboratory of Applied Toxinology (LETA), Center of Toxins, Immune Response and Cell Signaling (CETICS), Butantan Institute, São Paulo 05503-900, Brazil., Presoto BC; Pharmacology Laboratory, Butantan Institute, São Paulo 05503-900, Brazil., Guimaraes AO; Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Pesquero JB; Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil., Bader M; Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin, Germany.; Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.; Berlin Institute of Health (BIH), 10117 Berlin, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany.; Institute for Biology, University of Lübeck, 23538 Lübeck, Germany., Castro LM; Biosciences Institute, São Paulo State University (UNESP), 11330-900 São Vicente, SP, Brazil., Ferro ES; Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil. eferro@usp.br.
Jazyk: angličtina
Zdroj: Biomolecules [Biomolecules] 2019 Aug 19; Vol. 9 (8). Date of Electronic Publication: 2019 Aug 19.
DOI: 10.3390/biom9080382
Abstrakt: 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.
Competing Interests: The authors declare no conflicts of interest.
Databáze: MEDLINE
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