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

Santos, Nilton Barreto dos; Franco, Roseane D.; Camarini, Rosana; Eichler, Rosangela Aparecida dos Santos; Gewehr, Mayara C.F.; Reckziegel, Patrícia; Llanos, Ricardo Pariona; Dale, Camila S.; Silva, Victoria R. O. da; Borges, Vanessa; Lima, Bráulio Henrique Freire; Cunha, Fernando Q.; Visniauskas, Bruna; Chagas, Jair Ribeiro; Tufik, Sérgio; Peres, Fernanda Fiel; Abı́lio, Vanessa C.; Flório, Jorge Camilo; Iwai, Leo Kei; Rioli, Vanessa; Presoto, Benedito C.; Guimaraes, Alessander O.; Pesquero, João Bosco; Bäder, Michael; Castro, Leandro M.; Ferro, Emer S.

doi:10.3390/biom9080382

Cited by 24 publications

(39 citation statements)

References 129 publications

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“…The molecular mechanism supporting the distinctive phenotypes of THOP1 −/− mice possibly involves intracellular peptides [54]. Anorexigenic and orexigenic neuropeptides have not previously been characterized as THOP1 substrates [49] and, here, the levels of hormonal peptides related to obesity were shown to be unaffected in THOP1 −/− animals.…”

Section: Discussionmentioning

confidence: 56%

“…These data were recently corroborated by THOP1 C57BL6 null mice (THOP1 −/− ), which showed poor clinical scores compared to wild-type C57BL6 mice (WT) in an autoimmune encephalomyelitis neurodegeneration model for multiple sclerosis [54]. THOP1 was also shown to have roles in sepsis, peripheral bradykinin metabolism related to the inflammatory pain response, and in affecting animal behaviors such as depression, attention, and memory retention [54]. Previous studies have associated THOP1 with distinct human pathologies [44,[55][56][57][58][59], including Alzheimer's disease [59] and early diabetic retinopathy [55].…”

Section: Introductionmentioning

confidence: 75%

“…A full detailed description of THOP1 −/− mice generation and genotyping procedures were previously described [54]. Briefly, the THOP1 gene trap knockout mouse strain was generated by blastocyst microinjection of genetically modified embryonic stem cells (CSG163, 129ola) that were obtained from BayGenomics through the International Gene Trap Consortium.…”

Section: Generating and Genotyping Thop1 −/− Micementioning

confidence: 99%

“…THOP1 has been established as one of the highly expressed genes related to epigenetic interactions in lung adenocarcinoma of poor prognosis [44]; it is also associated with MHC-I antigen presentation [26,27,[45][46][47] and the inactivation of several neuropeptides [41,42,[48][49][50][51][52][53]. These data were recently corroborated by THOP1 C57BL6 null mice (THOP1 −/− ), which showed poor clinical scores compared to wild-type C57BL6 mice (WT) in an autoimmune encephalomyelitis neurodegeneration model for multiple sclerosis [54]. THOP1 was also shown to have roles in sepsis, peripheral bradykinin metabolism related to the inflammatory pain response, and in affecting animal behaviors such as depression, attention, and memory retention [54].…”

Section: Introductionmentioning

confidence: 98%

“…THOP1 −/− was considered a unique animal model to induce changes only in the intracellular peptide profile without disturbing protein degradation, due to THOP1's well-characterized unconventional substrate-size restriction [21][22][23][24]62,69,70]. Moreover, THOP1 −/− mice were shown to be healthy and viable, in addition to having a normal external appearance, estrous cycle, and fertility [54]. Altogether, the results presented herein successfully suggest THOP1 is a novel target for controlling obesity and associated diseases.…”

Section: Introductionmentioning

confidence: 99%

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The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

et al. 2020

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Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1−/−) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1−/− and WT mice ingested similar chow and calories; however, the THOP1−/− mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1−/− mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1−/− fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1−/− mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 75%

Section: Generating and Genotyping Thop1 −/− Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

et al. 2020

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Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease: A cross‐platform validation study

Hok‐A‐Hin

Bolsewig

Ruiters

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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INTRODUCTIONOur previous antibody‐based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI‐Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large‐scale analysis and validate our proteomics findings in two independent cohorts.METHODSWe developed in‐house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing–Bablok regression analysis in a subset of CSF samples from the discovery cohort (n = 72). Clinical validation was performed in two independent cohorts (cohort 1: n = 200; cohort 2: n = 165) using the Ella platform.RESULTSTHOP1 concentrations moderately correlated between proteomics analysis and our novel assays (Rho > 0.580). In both validation cohorts, CSF THOP1 was increased in MCI‐Aβ+ (>1.3‐fold) and AD (>1.2‐fold) compared with controls; and between MCI‐Aβ+ and DLB (>1.2‐fold). Higher THOP1 concentrations were detected in AD compared with DLB only when both cohorts were analyzed together. In both cohorts, THOP1 correlated with CSF total tau (t‐tau), phosphorylated tau (p‐tau), and Aβ40 (Rho > 0.540) but not Aβ42.DISCUSSIONValidation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody‐based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid‐based biomarkers.

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Methods for Intracellular Peptidomic Analysis

Eichler,

Martucci,

de Castro

et al. 2024

Methods in Molecular Biology

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

Cited by 24 publications

References 129 publications

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease: A cross‐platform validation study

Methods for Intracellular Peptidomic Analysis

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