Elsevier

Schizophrenia Research

Volume 208, June 2019, Pages 202-208
Schizophrenia Research

Ndel1 oligopeptidase activity as a potential biomarker of early stages of schizophrenia

https://doi.org/10.1016/j.schres.2019.02.021Get rights and content

Abstract

Our previous studies showed reduced Ndel1 enzyme activity in patients with chronic schizophrenia (SCZ), and only a subtle NDEL1 mRNA increases in antipsychotic-naïve first-episode psychosis (FEP) individuals compared to matched healthy controls (HC). Aiming to refine the evaluation of Ndel1 enzyme activity in early stages of psychosis, we compared 3 groups composed by (1) subjects at ultra-high-risk (UHR) for psychosis, (2) a cohort comprising antipsychotic-naïve FEP individuals (assessed in three moments, at baseline (FEP-0), and after 2 months (FEP-2 M) and one year (FEP-1Y) of treatment with risperidone), and (3) a HC group. There was no significant difference in Ndel1 enzyme activity between UHR and HC, but this activity was significantly lower in FEP compared to HC. Conversely, Ndel1 activity in HC groups was higher than in FEP even before (FEP-0) or after the treatment with risperidone (FEP-2 M and FEP-1Y), and with progressive decrease of Ndel1 activity and significant improvement of symptoms observed after this treatment. In addition, a positive correlation was observed for Ndel1 activity with clinical symptoms as assessed by PANSS, while a negative correlation was seen for GAF scores. Our results suggest that reductions in Ndel1 activity in FEP may be possibly related to responses to the illness, rather than to the pharmacological effects of antipsychotics, which might be acting essentially in the symptoms suppression. This hypothesis might be further evaluated in prospective long-term follow-up studies with a larger sample cohort.

Introduction

In the last decade, scientific research in psychosis has experienced a major shift in its focus, and a better understanding of the trajectories from normal development to the first manifestations allowing the diagnosis of schizophrenia (SCZ) was found to offer new insight in the possibility of prevention. One of the most well established strategy to investigate early illness trajectories in psychosis is to evaluate putative prodromal stage also known as ultra-high risk (UHR) for psychosis, which may be composed by individuals who are genetically predisposed to psychosis due to a first degree relative affected by mental disorder or by any population presenting sub-threshold SCZ symptoms that may be detectable weeks, months or even years before the first episode of psychosis (FEP) (Yung and McGorry, 1996; Yung et al., 1998; Yung et al., 2005). The assessment of individuals in FEP, especially before the confounder effect of antipsychotic medications, is also crucial to evaluate the disorder progression and to identify reliable biomarkers of illness progression.

SCZ trajectory is shaped by a multifactorial combination of genetic and environmental factors continually influencing the neurodevelopment and neuroprogression (Davis et al., 2014; Stein and Broome, 2015). Several risk genes potentially associated to SCZ have been identified, and Disrupted-in-Schizophrenia 1 (DISC1) gene is among the most investigated genetic factor (Brandon and Sawa, 2011; Niwa et al., 2016; Tomoda et al., 2017; Dahoun et al., 2017). The major ligand of the DISC1 protein product is the nuclear distribution element-like 1 (Ndel1), which possesses enzyme activity and cleaves neuropeptides as bradykinin and neurotensin that also have essential roles in neurogenesis and antipsychotic response, respectively (Hayashi et al., 2005; Camargo et al., 2007; Hayashi et al., 2015; Bradshaw and Hayashi, 2017). Ndel1 and DISC1 complex formation is critical for neuritogenesis, neurite outgrowth and neuronal migration (Ozeki et al., 2004; Duan et al., 2007; Hayashi et al., 2010; Bradshaw and Hayashi, 2017). Failures in Ndel1/DISC1 interactions can affect the formation of brain structures during embryogenesis (Kamiya et al., 2005; Kamiya et al., 2006; Bradshaw and Hayashi, 2017). Interestingly, the Ndel1-DISC1 complex formation also modulates Ndel1 enzyme activity (Hayashi et al., 2005), whose suppression was demonstrated to decrease neurite outgrowth in vitro (Hayashi et al., 2010; Bradshaw and Hayashi, 2017).

Previous studies of the group showed subtle NDEL1 mRNA increases in FEP individuals compared to healthy controls (HC) (Ota et al., 2015), while reduced Ndel1 enzyme activity was demonstrated by us in chronic SCZ patients with no significant association to any specific clinical aspects or to the employed antipsychotics (Gadelha et al., 2013). Considering the low Ndel1 activity in chronic SCZ, we hypothesized a possible progressive decrease of Ndel1 activity among HC, UHR and FEP subjects, with a relative improvement in FEP after risperidone treatment.

Therefore, the objective of this study was to evaluate and compare the Ndel1 oligopeptidase activity levels in three different groups, namely HC, UHR for psychosis, and antipsychotic-naïve FEP individuals, who were also assessed along the treatment with risperidone. In addition, we investigated the Ndel1 activity levels as a possible biomarker of early stages of SCZ and the association of Ndel1 activity levels with symptoms severity before and after the treatment with risperidone.

Section snippets

Subjects

This study was approved by the Research Ethics Committee of UNIFESP [CEP No. 1427/16]. A written informed consent was obtained from all participants or their representatives, prior their inclusion. Clinical and laboratory investigations were strictly conducted according to the principles expressed in the Declaration of Helsinki.

Exclusion criteria were the same for all groups, as listed: (i) presence of neurological and general medical comorbidities, (ii) history of brain traumatic injury, (iii)

Demographic characteristics of the groups

The UHR group was composed by 15 individuals, from which 12 were classified as attenuated positive symptoms (APS), one presented brief and intermittent psychotic symptoms (BLIPS), and one patient was reported to have genetic risk plus functional decline in the last year (HDec). At the blood collection time, 6 UHR subjects were under the use of anti-depressive or antipsychotic medication, while other 9 individuals were not medicated. In the following 2-years after the first assessment, only 3

Discussion

Aiming to evaluate the Ndel1 activity in each stages of illness, Ndel1 enzyme activity was measured in UHR for psychosis and in antipsychotic-naïve FEP individuals. Despite the absence of significant differences between the UHR and HC groups, lower Ndel1 enzyme activity in FEP individuals compared to HC was shown for the first time at baseline (FEP-0) and also after treatment. In fact, Ndel1 activity decreased after 2 months (FEP-2 M) and one year of treatment (FEP-1Y) in parallel with the

Author contribution

Caroline Dal Mas – performed experiments, data analyses and participation in writing.

João V. Nani – data analysis and participation in writing.

Cristiano Noto – recruitment and clinical evaluation of FEP patients.

Camila M. Yonamine – processing of samples and performed experiments.

Graccielle Rodrigues da Cunha – recruitment and clinical evaluation of UHR patients and databank management.

Rodrigo B. Mansur – data analysis.

Vanessa K. Ota – processing of blood samples and final revision of the text.

Conflict of interest

The authors declare no conflicts of interest.

Financial disclosures

Camila M. Yonamine and Vanessa. K. Ota were recipient of a fellowship from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo). Ary Gadelha and Cristiano Noto received CAPES fellowship. Caroline Dal Mas and João V. Nani received CNPq fellowship. Quirino Cordeiro, Sintia Belangero, Rodrigo A Bressan and Mirian AF Hayashi are all supported by FAPESP, CAPES and/or CNPq. Dr. MAF Hayashi is also the recipient of a fellowship from CNPq [3/2012-0, 475739/2013-2 and 39337/2016-0] and receives

Acknowledgments

This work was supported by the São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP) (No. 2011/50740-5 for R.A.B, No. 2013/13392-4 for M.A.F.H., and No. 2009/51587-6 for both R.A.B and M.A.F.H and No. 2012/08941-6 for C.M.Y) and the National Council of Technological and Scientific Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq) (477760/2010-4; 557753/2010-4; 508113/2010-5; 311815/2012-0; 475739/2013-2 for M.A.F.H).

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      NDEL1 also has diverse functions of particular importance for the development of the cerebral cortex, acting for instance, in the regulation of mitotic spindles and neuronal positioning (Feng and Walsh, 2004; Shu et al., 2004), and also as a modulator of neuropeptide neurotransmitters signaling involved in SCZ (Bradshaw and Hayashi, 2017). Much of the research involving NDEL1 in psychiatric disorders comes from studies investigating the protein-protein interactions of NDEL1 with DISC1 and with other cytosolic proteins (Burdick et al., 2008; Johnstone et al., 2015; Kamiya et al., 2006; Tomppo et al., 2009), which was especially reinforced by the demonstration of changed NDEL1 enzyme activity in several psychiatric patients (Gadelha et al., 2013; Dal Mas et al., 2019a, b). DISC1 was initially suggested as a potential susceptibility gene for psychiatric disorders due to the segregation of a balanced translocation of DISC1, with SCZ and affective disorders in a large Scottish family (Millar et al., 2000).

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