Caracterização do papel das endopeptidases (ndel1 e da eca) na esquizofrenia: um estudo translacional e multimodal

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Araripe Neto, Ary Gadelha de Alencar [UNIFESP]
Bressan, Rodrigo Affonseca Bressan [UNIFESP]
Tese de doutorado
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Background: NDEL1 oligopeptidase interacts with schizophrenia (SCZ) risk gene product DISC1 and mediates several functions related to neurite outgrowth and neuronal migration. NDEL1 also hydrolyses neuropeptides previously implicated in SCZ, namely neurotensin and bradykinin. Methodology: Herein, we compared the plasma NDEL1 enzyme activity of 92 SCZ patients and 96 healthy controls (HCs). NDEL1 enzyme activity was determined by fluorimetric measurements of the FRET peptide substrate Abz-GFSPFRQ-EDDnp hydrolysis rate. Results: A 31% lower mean value for NDEL1 activity was observed in SCZ patients compared to HCs (Student’s t = 4.36; p < 0.001; Cohen’s d = 0.64). The Area Under the Curve (AUC) for the Receiver Operating Characteristic (ROC) curve for NDEL1 enzyme activity and SCZ/HCs status as outcome was 0.70. Treatmentresistant (TR) SCZ patients were shown to present a significantly lower NDEL1 activity compared to non-TR (NTR) patients by t-test analysis (t = 2.25; p = 0.027). A lower enzymatic activity was significantly associated with both NTR (p = 0.002; B = 1.19; OR = 3.29; CI 95% 1.57-6.88) and TR patients (p < 0.001; B = 2.27; OR = 9.64; CI 95% 4.12-22.54). No correlation between NDEL1 enzyme activity and antipsychotic dose, nicotine dependence, and body mass index was observed. Conclusion: This study is the first to show differences in NDEL1 activity in SCZ patients compared to HCs, besides with a significant lower activity for TR patients compared to NTR patients. Our findings support the NDEL1 enzyme activity implications to clinical practice in terms of diagnosis and drug treatment of SCZ.
ARARIPE NETO, Ary Gadelha de Alencar. Caracterização do papel das endopeptidases (ndel1 e da eca) na esquizofrenia: um estudo translacional e multimodal. 2014. Tese (Doutorado) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2014.