Neuroproteomics as a Tool for Understanding Schizophrenia: A Tool for Understanding Schizophrenia

142 Pages·2022·6.001 MB·English

by  Daniel Martins-de-Souza

Advances in Experimental Medicine and Biology 1400
Proteomics, Metabolomics, Interactomics and Systems Biology
Daniel Martins-de-Souza   Editor
Neuroproteomics
as a Tool for
Understanding
Schizophrenia
Advances in Experimental Medicine
and Biology
Volume 1400
Series Editors
Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives
d’Aquitaine, CNRS and University of Bordeaux, Pessac Cedex, France
Haidong Dong, Departments of Urology and Immunology, Mayo Clinic,
Rochester, MN, USA
Heinfried H. Radeke, Institute of Pharmacology & Toxicology, Clinic of the
Goethe University Frankfurt Main, Frankfurt am Main, Hessen, Germany
Nima Rezaei, Research Center for Immunodeficiencies, Children’s Medical
Center, Tehran University of Medical Sciences, Tehran, Iran
Ortrud Steinlein, Institute of Human Genetics, LMU University Hospital,
Munich, Germany
Junjie Xiao, Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Science, School of Life Science, Shanghai University,
Shanghai, China
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Daniel Martins-de-Souza
Editor
Neuroproteomics as a
Tool for Understanding
Schizophrenia
Editor
Daniel Martins-de-Souza
Institute of Biology, Laboratory of Neuroproteomics
University of Campinas (UNICAMP)
Campinas SP, Brazil
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISSN 2730-6216 ISSN 2730-6224 (electronic)
Proteomics, Metabolomics, Interactomics and Systems Biology
ISBN 978-3-030-97181-6 ISBN 978-3-030-97182-3 (eBook)
https://doi.org/10.1007/978-3-030-97182-3
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Preface
Schizophrenia is one of the most disabling diseases of humankind, alongside
with other psychiatric disorders. It affects about 20 million people world-
wide, and in the last few years, more than 1 million new cases are reported
every year. Schizophrenia is incurable, and most patients – generally young
adults – are incapable of working, studying, and having proper relationships
with their family and friends. Antipsychotic medication is the main way of
managing the disease, but its efficacy is debatable: a considerable number of
patients give up medication because of severe side effects in relation to poor
efficacy; in general, only part of the symptoms are managed and not all
patients considered good responders are able to live their lives as prior to the
disease.
All these hurdles are because schizophrenia still needs to be better under-
stood from a molecular perspective, despite all efforts in the past decades. In
the post-genomic era, proteomics has emerged as a tool to depict molecular
mechanisms through the large-scale analyses of expressed proteins and their
post-translational modifications, enabling the quantification of differentially
expressed proteins involved in a given disease and the connection of the dys-
functional biological processes and biochemical pathways. Generated data
have the potential to enlighten the molecular features of schizophrenia, which
could be helpful down the road for the development of innovative medication
and more effective treatment.
Proteomics has been largely explored by scientists involved in schizophre-
nia research in the last 20 years. Several laboratories across the globe engaged
on this regard, and most of these efforts are compiled here. In ten chapters,
authors approached proteomic studies (and metabolomics) in postmortem
brain tissue, animal, and cellular pre-clinical models and as well as in the
context of treatment, discussing how classical antipsychotics and newly pro-
posed treatments modulate protein expression in different brain cell types.
Knowledge contained in this book will help drawing new roads to be trav-
elled from here on in the search of molecular comprehension of schizophre-
nia. While these are rather basic information, distant for a clinical application,
they are indispensable to build strategies based in precision medicine con-
cepts which will in turn have an impact in patients’ lives.
Campinas, SP, Brazil Daniel Martins-de-Souza
v
Contents
Postmortem Brains: What Can Proteomics Tell us About
the Sources of Schizophrenia? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Guilherme Reis-de-Oliveira, Bradley J. Smith,
and Daniel Martins-de-Souza
What Can We Learn from Animal Models
to Study Schizophrenia? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Fernanda Crunfli, Caroline Brandão-Teles, Giuliana S. Zuccoli,
Adriano J. M. Chaves Filho, Gabriela Maciel Vieira,
Danyelle Silva-Amaral, José Alexandre Crippa,
João F. C. Pedrazzi, Danielle S. Macêdo, Elaine Del-Bel,
and Felipe V. Gomes
Modeling Schizophrenia In Vitro: Challenges and Insights
on Studying Brain Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Caroline Brandão-Teles, Giuliana S. Zuccoli, Bradley J. Smith,
Gabriela Maciel Vieira, and Fernanda Crunfli
Schizophrenia Outside the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Aline Gazzola Fragnani Valença and Bradley Joseph Smith
Molecular Features Triggered by Antipsychotic Medication
in Brain Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Lívia Ramos-da-Silva and André S. L. M. Antunes
Known and Unexplored Post- Translational Modification
Pathways in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Bradley J. Smith and Victor C. Carregari
Molecular Findings Guiding the Modulation
of the Endocannabinoid System as a Potential
Target to Treat Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Giuliana S. Zuccoli, Caroline Brandão-Teles,
Gabriela Maciel Vieira, Felipe V. Gomes,
and Fernanda Crunfli
Metabolomics: A Powerful Tool to Understand
the Schizophrenia Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Flávia da Silva Zandonadi, Emerson Andrade Ferreira dos Santos,
Mariana Silveira Marques, and Alessandra Sussulini
vii
viii Contents
Modulating Specific Pathways In Vitro to Understand
the Synaptic Dysfunction of Schizophrenia . . . . . . . . . . . . . . . . . . . . . 121
Verônica M. Saia-Cereda
Proteomics and Schizophrenia: The Evolution
of a Great Partnership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Bradley J. Smith, Victor C. Carregari,
and Daniel Martins-de-Souza
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Postmortem Brains: What Can
Proteomics Tell us About
the Sources of Schizophrenia?
Guilherme Reis-de-Oliveira, Bradley J. Smith,
and Daniel Martins-de-Souza
Contents
1 Schizophrenia: Multifactorial Disorders Require Multifaceted
Approaches 2
2 Proteomics and Postmortem Tissue: News About This Ideal Union 3
3 Bioinformatics: New Roads, New Perspectives 5
4 Knowledge: Sharing and Multiplying 9
5 Far Away from Conclusions 10
References 10
Abstract
Modeling schizophrenia is challenging due to
G. Reis-de-Oliveira (*) · B. J. Smith
Lab of Neuroproteomics, Department of the uniquely human component of psychiatric
Biochemistry and Tissue Biology, Institute of disorders. Despite several advances in cellular
Biology, University of Campinas (UNICAMP),
and animal modeling, postmortem brain tissue
Campinas, Brazil
derived from patients is still one of the
D. Martins-de-Souza
extremely few sources of information that
Lab of Neuroproteomics, Department of
comprises brain complexity, human genetics,
Biochemistry and Tissue Biology, Institute of
Biology, University of Campinas (UNICAMP), and patient experiences. Additionally, post-
Campinas, Brazil mortem tissue from patients with schizophre-
Instituto Nacional de Biomarcadores em nia can be used to drive hypotheses that can
Neuropsiquiatria (INBION) Conselho Nacional de then be validated in other models, involving
Desenvolvimento Científico e Tecnológico,
either other animals or an in vitro approach.
São Paulo, Brazil
While evaluating high-throughput and sensi-
Experimental Medicine Research Cluster (EMRC),
tive techniques, shotgun proteomics allows for
University of Campinas, Campinas, SP, Brazil
the identification and quantitation of thou-
D’Or Institute for Research and Education (IDOR),
sands of proteins present in biological
São Paulo, Brazil
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1
D. Martins-de-Souza (ed.), Neuroproteomics as a Tool for Understanding Schizophrenia,
Advances in Experimental Medicine and Biology 1400, https://doi.org/10.1007/978-3-030-97182-3_1
2 G. Reis-de-Oliveira et al.
systems. In the context of schizophrenia, organoids, and other similar models). Despite the
proteomics can map differentially regulated advances that have been made in creating more
proteins throughout brain regions of patients robust models, the diagnosis of schizophrenia
with schizophrenia, generating a large amount still relies on examining human-exclusive char-
of information regarding the disorder’s patho- acteristics through interviews between psychia-
physiology. In this chapter, our aim is to bring trists and patients, in which the latter will describe
the literature up to date regarding proteomics their view of the world to reveal personal delu-
tools applied to postmortem brains from sions, hallucinations, and other symptoms.
patients with schizophrenia, additionally dis- In addition to animal models, postmortem
cussing new findings, roads, and perspectives brains from patients with schizophrenia are com-
for the comprehension of this severe disorder. plex systems that can improve our knowledge
about this disorder since it allows us to obtain
Keywords molecular information directly from the brains of
patients that were diagnosed by specialized pro-
Psychiatry · Schizophrenia · Postmortem · fessionals. Postmortem brains also originated
Proteomics · Systems biology · Database from a complete biological system and therefore
present a higher degree of similarity to living
patients than induced animal models or in vitro
models. Overall, results from postmortem human
1 Schizophrenia: Multifactorial tissues can be used to complement existing and
Disorders Require support new hypotheses in other, more manage-
Multifaceted Approaches able, and environment-controlled models.
In order to get as much information as possi-
The spectrum of psychiatric disorders is com- ble from the rare and precious samples, that is,
posed of heterogeneous and multifactorial disor- postmortem brains from patients with schizo-
ders that comprise schizophrenia, bipolar phrenia, various “omic” tools have the potential
disorder, autism, and depression, among others to highlight new molecular features and path-
(Adam, 2013). Within this spectrum of disorders, ways that can be used, respectively, in biomarker
schizophrenia forms a pivotal category that pres- research and in drug discovery for novel
ents psychotic and negative prodromal and treatments. Shotgun proteomics identifies and
residual- phase symptoms lasting for over quantifies proteins in a given sample in an unbi-
6 months (Lieberman & First, 2018), in addition ased manner and is therefore, by definition, a
to lifelong symptoms affecting the central ner- powerful strategy to elucidate the molecular
vous system, periphery, and cognition. mechanisms of heterogeneous and multifactorial
Studying the molecular mechanisms associ- disorders. Quantitative proteomics is capable of
ated with – and potentially behind – the physio- measuring the abundance of thousands of pro-
pathology of schizophrenia is particularly teins among conditions in a single experiment,
challenging since studying and otherwise access- enabling a deeper investigation of protein abun-
ing the brains of living patients are limited by dance, turnover, spatiotemporal distribution,
ethical and practical reasons, even more so in post- translational modifications, and other char-
controlled conditions. In response to this diffi- acteristics (Bludau & Aebersold, 2020).
culty, several models have been developed to bet- This approach has been extensively used by
ter understand the various molecular aspects of many research groups around the world that have
this disorder, varying from complex systems (e.g. published original articles using proteomics with
in vivo models, using rats, mice, or other ani- postmortem brain samples from patients with
mals) to more biologically delimited systems schizophrenia. In 2017, our group reviewed the
(e.g. in vitro models, using immortalized cell literature published until then and, in doing so,
lines, induced pluripotent stem cells, cultured compiled proteomic results from studies using