Peptidomic analysis of the neurolysin-knockout mouse brain

Castro, Leandro M.; Cavalcanti, Diogo Manuel Lopes de Paiva; Araujo, Christiane B. de; Rioli, Vanessa; Icimoto, Marcelo Yudi; Gozzo, Fábio C.; Juliano, María A.; Juliano, Luiz; Oliveira, Vitor; Ferro, Emer S.

doi:10.1016/j.jprot.2014.03.043

Cited by 29 publications

(43 citation statements)

References 55 publications

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“…However, even after neuropeptide injection (bradykinin, angiotensin II, and neurotensin), KO and WT mice have similar behaviors in blood pressure alterations. A parallel study conducted in our laboratory suggested that Nln knock-out only affects the levels of Met-enkephalin and octapeptide and thus exerts only a minor effect on intracellular peptide metabolism in the brain (82). Altogether, these data suggest that other peptidases may efficiently compensate the lack of Nln in physiological neuropeptide metabolism.…”

Section: Ms Spectramentioning

confidence: 67%

Neurolysin Knockout Mice Generation and Initial Phenotype Characterization

Cavalcanti¹,

Castro

Neto³

et al. 2014

Journal of Biological Chemistry

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Background:Neurolysin is known to cleave several bioactive peptides in vitro. Results: Neurolysin knock-out mice showed increased glucose tolerance, insulin sensitivity, and gluconeogenesis, which likely relates to increased expression of both specific liver mRNAs and intracellular peptides. Conclusion: Neurolysin plays a role in energy metabolism. Significance: Neurolysin could be used as a therapeutic target to counteract insulin resistance.The oligopeptidase neurolysin (EC 3.4.24.16; Nln) was first identified in rat brain synaptic membranes and shown to ubiquitously participate in the catabolism of bioactive peptides such as neurotensin and bradykinin. Recently, it was suggested that Nln reduction could improve insulin sensitivity. Here, we have shown that Nln KO mice have increased glucose tolerance, insulin sensitivity, and gluconeogenesis. KO mice have increased liver mRNA for several genes related to gluconeogenesis. Isotopic label semiquantitative peptidomic analysis suggests an increase in specific intracellular peptides in gastrocnemius and epididymal adipose tissue, which likely is involved with the increased glucose tolerance and insulin sensitivity in the KO mice. These results suggest the exciting new possibility that Nln is a key enzyme for energy metabolism and could be a novel therapeutic target to improve glucose uptake and insulin sensitivity.

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Section: Ms Spectramentioning

confidence: 67%

Neurolysin Knockout Mice Generation and Initial Phenotype Characterization

Cavalcanti¹,

Castro

Neto³

et al. 2014

Journal of Biological Chemistry

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“…MS analysis detected 173 distinct peptides; 31 peptides showed a slight increase, while six peptides were decreased in neurolysin knockout mice when com pared to wildtype mouse. The results were interpreted as a minimal role of neurolysin in the regulation of intracel lular peptides in the mouse brain (Castro et al, 2014).…”

Section: Current Status Of Peptidomics In Proteolysis Studiesmentioning

confidence: 92%

“…An example of such a study is the investigation of the brain peptidome from neurolysin knockout mouse model in comparison to wildtype control mice (Castro et al, 2014). Neurolysin is an endooligopepti dase that cleaves a number of bioactive peptides including neurotensin and bradykinin.…”

Section: Current Status Of Peptidomics In Proteolysis Studiesmentioning

confidence: 99%

“…Neurolysin is an endooligopepti dase that cleaves a number of bioactive peptides including neurotensin and bradykinin. Extracted peptides from wild type and knockout mice were differentially labeled using stable isotopes of 4trimethylammoniumbutyryl (Castro et al, 2014). MS analysis detected 173 distinct peptides; 31 peptides showed a slight increase, while six peptides were decreased in neurolysin knockout mice when com pared to wildtype mouse.…”

Section: Current Status Of Peptidomics In Proteolysis Studiesmentioning

confidence: 99%

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The emerging role of the peptidome in biomarker discovery and degradome profiling

Lai

Petrera

Schilling³

2014

Biological Chemistry

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The peptidome represents the array of endogenous peptides that are present in both the intracellular and extracellular space of the body. Peptides are constantly generated in vivo by active synthesis, and by proteolytic processing of larger precursor proteins, often yielding protein fragments that mediate a variety of physiological functions. Given that aberrant proteolysis is a hallmark of various pathological diseases, many studies have now turned to the peptidome. Differential regulation of endogenous peptides may play a role in many pathological conditions. Mass spectrometry (MS) -based investigation of peptides in a system-wide manner is currently facilitating the identification of potential biomarkers. Furthermore, peptidomic approaches have provided major contributions to the identification of protease-substrate relationships; representing one of the major challenges in understanding and therapeutically exploiting protease function in health and disease. As such, degradomic studies looking for cleavage products via peptidomics in particular, have warranted a significant research interest in recent years. Given that substantial studies are accumulating in the field of peptidomics, this review highlights recent advances of MS-based peptidomic strategies in facilitating the identification of potential peptides as novel clinical markers and protease-substrate profiling.

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“…Examples of peptide actions include binding to proteins and activating or inhibiting their activity [11]. Peptidomic approaches have been used to examine the effects of proteasome inhibitors on the peptide content of HEK293T and SH-SY5Y cells [12] as well as in neurolysin-knockout mice [13] and in the identification of a new intracellular peptide, pep5-cpp, which reduced by 50% the volume of rat C6 glioblastoma [14].…”

Section: Introductionmentioning

confidence: 99%