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.