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The COVID-19 pandemic was initiated by the rapid spread of a SARS-CoV-2 strain. Though mainly classified as a respiratory disease, SARS-CoV-2 infects multiple tissues throughout the human body, leading to a wide range of symptoms in patients. To better understand how SARS-CoV-2 affects the proteome from cells with different ontologies, this work generated an infectome atlas of 9 cell models, including cells from brain, blood, digestive system, and adipocyte tissue. Our data shows that SARS-CoV-2 infection mainly trigger dysregulations on proteins related to cellular structure and energy metabolism. Despite these pivotal processes, heterogeneity of infection was also observed, highlighting many proteins and pathways uniquely dysregulated in one cell type or ontological group. These data have been made searchable online via a tool that will permit future submissions of proteomic data ( https://reisdeoliveira.shinyapps.io/Infectome_App/ ) to enrich and expand this knowledgebase.
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COVID-19 , SARS-CoV-2 , Humanos , Proteômica , PandemiasRESUMO
Long-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.
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COVID-19 , Microbioma Gastrointestinal , Animais , Camundongos , SARS-CoV-2 , Antibacterianos , Progressão da DoençaRESUMO
BACKGROUND: Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding the timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease. RESULTS: Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors (NPCs), early neurons, and brain organoids in comparison to healthy individuals. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis, we found multiple dysregulated proteins since NPCs, modified, and disrupted the 21DIV neuronal differentiation, and cerebral organoids. Our experimental methods have shown impairments in pathways never before found in patient-derived induced pluripotent stem cells studies, such as spliceosomes and amino acid metabolism; but also, those such as axonal guidance and synaptogenesis, in line with postmortem tissue studies of schizophrenia patients. CONCLUSION: In conclusion, here we provide comprehensive, large-scale, protein-level data of different neural cell models that may uncover early events in brain development, underlying several of the mechanisms within the origins of schizophrenia.
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Depression is a complex and multifactorial disease, affecting about 6.5% of the elderly population in what is referred to as late-life depression (LLD). Despite its public health relevance, there is still limited information about the molecular mechanisms of LLD. We analyzed the blood plasma of 50 older adults, 19 with LLD and 31 controls, through untargeted mass spectrometry, and used systems biology tools to identify biochemical pathways and biological processes dysregulated in the disease. We found 96 differentially expressed proteins between LLD patients and control individuals. Using elastic-net regression, we generated a panel of 75 proteins that comprises a potential model for determining the molecular signature of LLD. We also showed that biological pathways related to vesicle-mediated transport and voltage-dependent calcium channels may be dysregulated in LLD. These data can help to build an understanding of the molecular basis of LLD, offering an integrated view of the biomolecular alterations that occur in this disorder. SIGNIFICANCE: Major depressive disorder in the elderly, called late-life depression (LLD), is a common and disabling disorder, with recent prevalence estimates of 6.5% in the general population. Despite the public health relevance, there is still limited information about the molecular mechanisms of LLD. The findings in this paper shed light on LLD heterogeneous biological mechanisms. We uncovered a potential novel biomolecular signature for LLD and biological pathways related to this condition which can be targets for the development of novel interventions for prevention, early diagnosis, and treatment of LLD.
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Transtorno Depressivo Maior , Idoso , Canais de Cálcio , Humanos , Plasma , Proteínas , ProteômicaRESUMO
Modeling schizophrenia is challenging due to the uniquely human component of psychiatric disorders. Despite several advances in cellular and animal modeling, postmortem brain tissue derived from patients is still one of the extremely few sources of information that comprises brain complexity, human genetics, and patient experiences. Additionally, postmortem tissue from patients with schizophrenia can be used to drive hypotheses that can then be validated in other models, involving either other animals or an in vitro approach. While evaluating high-throughput and sensitive techniques, shotgun proteomics allows for the identification and quantitation of thousands of proteins present in biological systems. In the context of schizophrenia, proteomics can map differentially regulated proteins throughout brain regions of patients with schizophrenia, generating a large amount of information regarding the disorder's pathophysiology. In this chapter, our aim is to bring the literature up to date regarding proteomics tools applied to postmortem brains from patients with schizophrenia, additionally discussing new findings, roads, and perspectives for the comprehension of this severe disorder.
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Esquizofrenia , Animais , Autopsia , Encéfalo/metabolismo , Humanos , Proteômica , Esquizofrenia/metabolismoRESUMO
One of the challenges in studying neuropsychiatric disorders is the difficulty in accessing brain tissue from living patients. Schizophrenia is a chronic mental illness that affects 1% of the population worldwide, and its development stems from genetic and environmental factors. In order to better understand the pathophysiology underlying schizophrenia, the development of efficient in vitro methods to model this disorder has been required. In addition to several in vitro models, induced pluripotent stem cells (iPSCs) arose as a powerful tool, enabling access to the genetic background of the donor. Moreover, genetic modification of these cells can improve studies of specific dysfunctions observed in the pathophysiology of several neuropsychiatric disorders, not only schizophrenia. Here, we summarize which in vitro models are currently available and their applications in schizophrenia research, describing their advantages and limitations. These technologies in the cell culture field hold great potential to contribute to a better understanding of the pathophysiology of schizophrenia in an integrated manner, in addition to testing potential therapeutic interventions based on the genetic background of the patient.
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Células-Tronco Pluripotentes Induzidas , Esquizofrenia , Encéfalo , Técnicas de Cultura de Células/métodos , Humanos , Neurônios , Esquizofrenia/genéticaRESUMO
Post-translational modifications (PTMs) of proteins occur in all domains of life, affecting various structural and functional properties. Multiple methods can be used to study PTMs depending on the biological question, which can vary widely. Schizophrenia is a widespread brain disorder that possesses many known contributing environmental factors and hundreds of genetic risk factors; however, a full picture of the mechanisms behind how and why this disorder occurs and how it can be treated remains unknown. Various PTMs have been found to be differentially expressed in several pathways that are dysregulated in schizophrenia, as seen in cell line and animal models, postmortem brain tissue from people with schizophrenia, and biological fluids like blood, plasma, and cerebrospinal fluid. Despite recent advances, several pathways have been completely left undisturbed by PTMomics and show great promise for better understanding of protein dynamics in schizophrenia, how the disease state occurs, and how it may be better treated in future therapies.
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Encefalopatias , Esquizofrenia , Animais , Humanos , Processamento de Proteína Pós-Traducional , Proteínas/genética , Proteômica/métodos , Esquizofrenia/genéticaRESUMO
The mass spectrometer is an instrument that observes particular masses of molecules of interest. Over the past century, it has grown to become a highly sensitive and robust tool in laboratorial and clinical research to identify and quantify thousands of proteins in a given sample in an unbiased manner leading to the quick rise in its use. This unbiased and high-throughput nature is extremely important in discovery-based studies, since no preset targets can be selected, as is the case with several other proteomic methods. In studying multifactorial diseases such as schizophrenia, mass-spectrometry-based proteomics has been frequently used and new improvements to the technique have been quickly taken advantage of. Over the past 15 years, mass spectrometry has evolved greatly, and with it, the proteomic analyses and data have evolved. In this chapter, a brief history of the evolution of mass spectrometry is covered along with how schizophrenia research has grown alongside this valuable methodology.
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Proteômica , Esquizofrenia , Humanos , Espectrometria de Massas/métodos , Peso Molecular , Proteômica/métodos , Esquizofrenia/diagnósticoRESUMO
Several classes of post-translational modifications (PTMs) regulate various processes that occur during neurodevelopment. The first of these processes is the regulation of the cytoskeleton and cytoskeleton-associating proteins, responsible for the stability, reorganization, and binding of microtubules and actin filaments. Dysregulations in these PTMs lead to dysregulated brain volume and composition, structural defects, behavioral defects, and dendrite growth. The second class of processes involves gene regulation, from chromatin modulation to protein turnover and degradation. Proper gene expression during neurodevelopment is critical to ensure correctly matured cells; dysregulation of PTMs in these pathways leads to various altered morphological and behavioral phenotypes. The third class of processes that are affected by PTMs is cell signaling and signal transduction, vital to cell migration and axonal guidance. Neurodevelopment is a complex sequence of spatially and temporally regulated processes, and PTMs play important roles in this regulation. Most of the known modifications have yet to be studied in depth and much remains undiscovered about their roles in neurodevelopment and otherwise.
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Cromatina , Processamento de Proteína Pós-Traducional , Citoesqueleto de Actina , Encéfalo , CitoesqueletoRESUMO
Post-translational modifications (PTMs) have a strong impact on many proteins across all kingdoms of life, affecting multiple functional and chemical properties of their protein recipients. With increasing knowledge about their functions, targets, and biological effects, dysregulations in PTMs have been implicated in various dysfunctions and diseases. One such target are histones, which compose the majority of the protein component of chromatin and the modulation of the 30+ PTMs that are known to affect them can have profound effects on chromatin state, gene expression, and DNA repair. In this review, the histone targets of PTMs are compiled in the context of neurological disorders, highlighting their specific biological roles and any previously implicated dysregulations in several classes of brain disease. Better understanding the pathogenic dysregulations of PTMs in such disorders can help to better understand their causes, as well as open doors to new possibilities for biomarkers and therapeutic targets.