Analysis of oligopeptidase activity in Ndel1 conditional knockout mice

• Grant number: 24/15100-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2024
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Mirian Akemi Furuie Hayashi
• Grantee: Leonardo Basso de Souza
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/13112-8 - Study of molecular and cellular mechanisms involved in mental disorders: clinical and animal models analysis, AP.TEM

Abstract

Oligopeptidases play a fundamental role in the maturation and degradation of bioactive peptides, including hormones and neuropeptides. These enzymes act only on oligopeptides, generally of 8 to 13 amino acids, but they do not cleave larger proteins and do not present primary specificity like classical enzymes/proteases. The activity of oligopeptidases has been widely studied in mental disorders mainly by this research group. For example, the oligopeptidase NudE Neurodevelopment Protein 1 Like 1 (Ndel1), with demonstrated importance in neurodevelopment, and Prolyl Oligopeptidase (POP), with demonstrated importance in neurodegenerative diseases, present altered activity in patients with psychiatric disorders and in animal models for study of these pathologies, demonstrating the importance of evaluating these enzymes in the context of mental disorders, such as schizophrenia, autism, bipolar disorder, depression, among others. Another oligopeptidase also widely studied in this context is Angiotensin I Converting Enzyme (ACE). Although initially described due to its crucial role in the generation of the hypertensive agent angiotensin II, which acts mainly in the regulation of peripheral blood pressure, this oligopeptidase also has functions in the central nervous system (CNS), having been associated with cognitive functions and neuroinflammation. . Although increased ACE activity has also been reported in psychiatric disorders, little is known about the involvement of these enzymes in these mental disorders, just as little is known about the interaction between these oligopeptidases under physiological conditions. Thus, this project aims to analyze the activity of POP and ACE oligopeptidases in different regions of the brain (including the cerebellum, prefrontal cortex, dorsal striatum and hippocampus) of conditional knockout (cKO) mice for Ndel1, aiming to understand how Suppression in the expression of Ndel1 oligopeptidase would affect the activity of other oligopeptidases in the CNS that share the same substrates. Therefore, we hope that this project will allow us to elucidate the effects and influence of low Ndel1 activity, as observed in patients with schizophrenia or bipolar disorder, on POP and ACE activity in different regions of the brain.