Descrição
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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
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.
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
Department of Anatomy, Biomedical Sciences Institute, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil
Department of Pharmacology Faculty of Medicine of Ribeirao Preto University of São Paulo
Department of Psychobiology, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil
Department of Pathology, Veterinarian Medical School, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil
Special Laboratory of Applied Toxinology (LETA) Center of Toxins Immune Response and Cell Signaling (CETICS) Butantan Institute
Pharmacology Laboratory Butantan Institute
Department of Biophysics, Federal University of São Paulo (UNIFESP), São Paulo 04023-062, SP, Brazil
Max-Delbrück-Center for Molecular Medicine
Charité - Universitätsmedizin Berlin
Berlin Institute of Health (BIH)
DZHK (German Center for Cardiovascular Research), Partner Site Berlin
Institute for Biology University of Lübeck
Biosciences Institute, São Paulo State University (UNESP), 11330-900 São Vicente, SP, Brazil
FAPESP: 2004/04933-2
FAPESP: 2016/04000-3
CNPq: 445363/2014-2, 400944/2014-6, 302809/2016-3, 150077/2015-7 and 449390-4
