O papel da Oligopeptidase Ndel1 no neurodesenvolvimento e transtornos mentais como a esquizofrenia, transtorno bipolar e o transtorno do espectro autista
Data
2023-12-11
Tipo
Tese de doutorado
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Resumo
Os transtornos mentais (TMs) são altamente prevalentes e clinicamente debilitantes, resultando de disfunções no sistema nervoso central. O trabalho do grupo tem sido focado em compreender as alterações associadas a diferentes transtornos, como a esquizofrenia (ESQ), o transtorno bipolar (TB), entre outros, que compartilham semelhanças na etiologia e em sintomas clínicos, por meio da avaliação do papel das oligopeptidases na suscetibilidade e na progressão desses transtornos. Neste trabalho, realizamos avaliações bioquímicas, moleculares, celulares e comportamentais em modelos com características relacionadas aos TMs. Nosso objetivo é estudar os mecanismos reguladores da atividade da oligopeptidase Ndel1 (Nuclear distribution element like-1), que se destaca como um potencial biomarcador para o diagnóstico de diferentes doenças do cérebro e como potencial ferramenta importante para avaliar a terapia de TMs. Mostramos previamente que a atividade da Ndel1 diminui em pacientes com ESQ e também em um modelo animal para o estudo da ESQ, após o tratamento com antipsicóticos, e com associação com a melhora de sintomas e/ou reversão do comportamento ESQ-símile. Utilizando um modelo animal transgênico superexpressando o gene humano DISC1 (Disrupted-in-Schizophrenia 1) humano íntegro e não mutante (tgDISC1), que reproduz a formação de agregados proteicos de DISC1, observados em amostras post-mortem de cérebro de pacientes com TMs, descrevemos a correlação entre a atividade reduzida de Ndel1, as alterações comportamentais e o posicionamento alterado de neurônios em diferentes regiões cerebrais. Observamos que a administração de uma subdose de anfetamina aumenta a atividade da Ndel1 em animais tgDISC1 e células de neuroblastoma humano SK-N-AS, sugerindo um envolvimento da Ndel1 na regulação de vias dopaminérgicas. No entanto, o antipsicótico atípico clozapina não afetou a atividade da Ndel1 nem reverteu as alterações comportamentais nos animais tgDISC1. Em um estudo clínico duplo-cego randomizado, observamos redução significativa da atividade da Ndel1 em pacientes com ESQ crônica após a administração do nitroprussiato de sódio (sNP) que determina melhora dos sintomas clínicos, oferecendo uma abordagem inovadora para os pacientes resistentes aos antipsicóticos empregados na clínica. Também demonstramos que a diminuição da atividade Ndel1 correlaciona com menor volume cerebral, em modelos de déficit no neurodesenvolvimento como a síndrome congênita do vírus Zika (ZIKV), e que pode levar à microcefalia. Além disso, realizamos a avaliação bioquímica/molecular de organóides cerebrais humanos derivados de iPSCs de pacientes com Transtorno do Espectro Autista (TEA) e controles saudáveis, observando menor atividade e expressão de Ndel1 nos organóides de pacientes com TEA, sugerindo que a correlação negativa entre a atividade e expressão de Ndel1 e o tamanho dos organoides possa indicar um papel para a Ndel1 nesse fenótipo específico. O presente estudo fortalece a Ndel1 como potencial alvo para pesquisas em TMs relacionados ao neurodesenvolvimento, destacando a sua importância também em respostas a intervenções farmacológicas diversas, embora mais estudos ainda sejam necessários para a melhor compreensão do papel da Ndel1 nesses contextos.
Mental disorders (MDs) are highly prevalent and clinically debilitating conditions resulting from dysfunctions in the central nervous system. Our group's work has been focused on understanding the changes associated with different disorders, such as schizophrenia (SZ), bipolar disorder (BD), among others, which share similarities in etiology and clinical symptoms, through the evaluation of the role of oligopeptidases in the susceptibility and progression of these disorders. In this study, we conducted biochemical, molecular, cellular, and behavioral assessments in models with features related to MDs. Our goal is to study the regulatory mechanisms of the activity of Ndel1 (Nuclear distribution element like-1) oligopeptidase, which stands out as a potential biomarker for the diagnosis of various brain diseases and as a potential important tool for TM therapy. We previously demonstrated that Ndel1 activity decreases in patients with SZ and also in an animal model for the study of SZ, after treatment with antipsychotics, and with an association with symptom improvement and/or reversal of SZ-like behavior. Using a transgenic animal model overexpressing the intact and non-mutated human DISC1 (Disrupted-in-Schizophrenia 1) gene (tgDISC1), which reproduces the formation of DISC1 protein aggregates observed in post-mortem brain samples from MD patients, we described the correlation between reduced Ndel1 activity, behavioral changes, and altered positioning of neurons in different brain regions. We observed that the administration of a subdose of amphetamine increased Ndel1 activity in tgDISC1 animals and human neuroblastoma cells (SK-N-AS), suggesting Ndel1 involvement in the regulation of dopaminergic pathways. However, the atypical antipsychotic clozapine did not affect Ndel1 activity or reverse behavioral changes in tgDISC1 animals. In a randomized double-blind clinical study, we observed a significant reduction in Ndel1 activity in patients with chronic SZ after the administration of sodium nitroprusside (SNP), which resulted in clinical symptom improvement, offering an innovative approach for patients resistant to antipsychotics used in clinical practice. We also demonstrated that decreased Ndel1 activity correlates with smaller brain volume in models of neurodevelopmental deficits such as congenital Zika virus (ZIKV) syndrome, which can lead to microcephaly. Furthermore, we conducted biochemical/molecular evaluation of human brain organoids derived from iPSCs of patients with Autism Spectrum Disorder (ASD) and healthy controls, observing lower Ndel1 activity and expression in organoids from ASD patients, suggesting that the negative correlation between Ndel1 activity and expression and organoid size may indicate a role for Ndel1 in this specific phenotype. This study strengthens Ndel1 as a potential target for research in MDs related to neurodevelopment, highlighting its importance in response to various pharmacological interventions, although further studies are still needed for a better understanding of the role of Ndel1 in these contexts.
Mental disorders (MDs) are highly prevalent and clinically debilitating conditions resulting from dysfunctions in the central nervous system. Our group's work has been focused on understanding the changes associated with different disorders, such as schizophrenia (SZ), bipolar disorder (BD), among others, which share similarities in etiology and clinical symptoms, through the evaluation of the role of oligopeptidases in the susceptibility and progression of these disorders. In this study, we conducted biochemical, molecular, cellular, and behavioral assessments in models with features related to MDs. Our goal is to study the regulatory mechanisms of the activity of Ndel1 (Nuclear distribution element like-1) oligopeptidase, which stands out as a potential biomarker for the diagnosis of various brain diseases and as a potential important tool for TM therapy. We previously demonstrated that Ndel1 activity decreases in patients with SZ and also in an animal model for the study of SZ, after treatment with antipsychotics, and with an association with symptom improvement and/or reversal of SZ-like behavior. Using a transgenic animal model overexpressing the intact and non-mutated human DISC1 (Disrupted-in-Schizophrenia 1) gene (tgDISC1), which reproduces the formation of DISC1 protein aggregates observed in post-mortem brain samples from MD patients, we described the correlation between reduced Ndel1 activity, behavioral changes, and altered positioning of neurons in different brain regions. We observed that the administration of a subdose of amphetamine increased Ndel1 activity in tgDISC1 animals and human neuroblastoma cells (SK-N-AS), suggesting Ndel1 involvement in the regulation of dopaminergic pathways. However, the atypical antipsychotic clozapine did not affect Ndel1 activity or reverse behavioral changes in tgDISC1 animals. In a randomized double-blind clinical study, we observed a significant reduction in Ndel1 activity in patients with chronic SZ after the administration of sodium nitroprusside (SNP), which resulted in clinical symptom improvement, offering an innovative approach for patients resistant to antipsychotics used in clinical practice. We also demonstrated that decreased Ndel1 activity correlates with smaller brain volume in models of neurodevelopmental deficits such as congenital Zika virus (ZIKV) syndrome, which can lead to microcephaly. Furthermore, we conducted biochemical/molecular evaluation of human brain organoids derived from iPSCs of patients with Autism Spectrum Disorder (ASD) and healthy controls, observing lower Ndel1 activity and expression in organoids from ASD patients, suggesting that the negative correlation between Ndel1 activity and expression and organoid size may indicate a role for Ndel1 in this specific phenotype. This study strengthens Ndel1 as a potential target for research in MDs related to neurodevelopment, highlighting its importance in response to various pharmacological interventions, although further studies are still needed for a better understanding of the role of Ndel1 in these contexts.