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1.
Artigo em Inglês | MEDLINE | ID: mdl-33850037

RESUMO

OBJECTIVE: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a severe immune-mediated disorder. We aim to report the neurologic features of children with PIMS-TS. METHODS: We identified children presenting to a large children's hospital with PIMS-TS from March to June 2020 and performed a retrospective medical note review, identifying clinical and investigative features alongside short-term outcome of children presenting with neurologic symptoms. RESULTS: Seventy-five patients with PIMS-TS were identified, 9 (12%) had neurologic involvement: altered conciseness (3), behavioral changes (3), focal neurology deficits (2), persistent headaches (2), hallucinations (2), excessive sleepiness (1), and new-onset focal seizures (1). Four patients had cranial images abnormalities. At 3-month follow-up, 1 child had died, 1 had hemiparesis, 3 had behavioral changes, and 4 completely recovered. Systemic inflammatory and prothrombotic markers were higher in patients with neurologic involvement (mean highest CRP 267 vs 202 mg/L, p = 0.05; procalcitonin 30.65 vs 13.11 µg/L, p = 0.04; fibrinogen 7.04 vs 6.17 g/L, p = 0.07; d-dimers 19.68 vs 7.35 mg/L, p = 0.005). Among patients with neurologic involvement, these markers were higher in those without full recovery at 3 months (ferritin 2284 vs 283 µg/L, p = 0.05; d-dimers 30.34 vs 6.37 mg/L, p = 0.04). Patients with and without neurologic involvement shared similar risk factors for PIMS-TS (Black, Asian and Minority Ethnic ethnicity 78% vs 70%, obese/overweight 56% vs 42%). CONCLUSIONS: Broad neurologic features were found in 12% patients with PIMS-TS. By 3-month follow-up, half of these surviving children had recovered fully without neurologic impairment. Significantly higher systemic inflammatory markers were identified in children with neurologic involvement and in those who had not recovered fully.


Assuntos
/complicações , Inflamação/complicações , Doenças do Sistema Nervoso/etiologia , Síndrome de Resposta Inflamatória Sistêmica/complicações , Adolescente , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , /psicologia , Criança , Transtornos do Comportamento Infantil/epidemiologia , Transtornos do Comportamento Infantil/etiologia , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Inflamação/patologia , Imagem por Ressonância Magnética , Masculino , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/psicologia , Estudos Retrospectivos , Síndrome de Resposta Inflamatória Sistêmica/patologia , Síndrome de Resposta Inflamatória Sistêmica/psicologia , Trombose/sangue , Trombose/etiologia
2.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803178

RESUMO

Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.


Assuntos
Proteínas de Transporte/metabolismo , Síndrome Metabólica , Neoplasias , Doenças do Sistema Nervoso , Proteínas Supressoras de Tumor/metabolismo , Animais , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/terapia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Síndrome Metabólica/terapia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/terapia , Proteínas Nucleares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/metabolismo , Tiorredoxinas/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802091

RESUMO

Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.


Assuntos
Doenças Autoimunes/terapia , Diabetes Mellitus/terapia , Doenças do Sistema Nervoso/terapia , Doenças Autoimunes/patologia , Diabetes Mellitus/patologia , Humanos , Doenças do Sistema Nervoso/patologia
4.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800815

RESUMO

In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson's disease, and Alzheimer's disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.


Assuntos
Descoberta de Drogas/métodos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Doenças do Sistema Nervoso/tratamento farmacológico , Organoides/efeitos dos fármacos , Animais , Automação , Encéfalo/citologia , Sistemas CRISPR-Cas , Técnicas de Cultura de Células , Colágeno , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/organização & administração , Previsões , Ensaios de Triagem em Larga Escala , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Laminina , Aprendizado de Máquina , Microscopia/métodos , Doenças do Sistema Nervoso/patologia , Proteoglicanas , RNA-Seq , Reprodutibilidade dos Testes , Análise de Célula Única
5.
Cells ; 10(2)2021 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668514

RESUMO

As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.


Assuntos
/complicações , Vesículas Extracelulares/patologia , Doenças do Sistema Nervoso/etiologia , Adulto , Idoso , Peptídeos beta-Amiloides/análise , Biomarcadores/análise , Biomarcadores/sangue , /patologia , Feminino , Humanos , Imunoglobulina G/sangue , Interleucina-4/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/patologia , Proteínas de Neurofilamentos/análise , Neurogranina/análise , Neurônios/patologia , Proteínas tau/análise
6.
Medicine (Baltimore) ; 100(9): e24687, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655933

RESUMO

RATIONALE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid deposition disorder characterized by systemic signs and neurological dysfunction. The radiological features of CTX are infrequently summarized in the literature. PATIENT CONCERNS: We described a 40-year-old male patient who repeatedly engaged in wrestling matches and presented with progressive difficulty in walking and reduced balance with egg-sized, hard, smooth, and painless masses in both ankles. DIAGNOSIS: Neuroimaging examination showed abnormalities both supra- and infratentorially. Bilateral ankle joint magnetic resonance imaging showed bilateral xanthomata of the Achilles tendon. The diagnosis was confirmed by the detection of a sterol 27-hydroxylase gene mutation. INTERVENTIONS: The patient was treated with chenodeoxycholic acid (250 mg 3 times per day). OUTCOMES: To date, the patient's bilateral xanthomas of the Achilles tendon have begun to diminish, and his neurological impairment has not deteriorated further but has not yet improved. LESSONS: We report a rare case of CTX and summarize the clinical and imaging features of this disease. Our findings suggest that the abnormal signals in the dentate nucleus or a long spinal cord lesion involving the central and posterior cord, combined with tendon xanthoma, are important clues for the diagnosis of CTX.


Assuntos
Imagem por Ressonância Magnética/métodos , Doenças do Sistema Nervoso/congênito , Xantomatose Cerebrotendinosa/complicações , Tendão do Calcâneo/diagnóstico por imagem , Tendão do Calcâneo/patologia , Adulto , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/patologia , Ácido Quenodesoxicólico/uso terapêutico , Humanos , Masculino , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/patologia , Xantomatose Cerebrotendinosa/diagnóstico por imagem , Xantomatose Cerebrotendinosa/patologia
7.
APMIS ; 129(5): 241-253, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33683784

RESUMO

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral germline infections. Most HERV sequences are silenced in somatic cells, but interest is emerging on the involvement of HERV derived transcripts and proteins in human physiology and disease. A HERV-W encoded protein, syncytin-1, has been co-opted into fetal physiology, where it plays a role in trophoblast formation. Altered HERV transcription and expression of HERV derived proteins are associated with various cancer types and neurological diseases such as multiple sclerosis (MS). The implication of HERVs as potential mediators of both health and disease suggests important roles of regulatory mechanisms and alterations of these in physiological and pathological processes. The regulation of HERV sequences is mediated by a wide variety of mechanisms, and the focus of this review is on selected aspects of these, including epigenetic mechanisms such as CpG methylation and histone modifications of the HP1-H3K9me axis, viral transactivation events, and regulatory perspectives of transient stimuli in the microenvironment. Increasing knowledge of the regulation of HERV sequences will not only contribute to the understanding of complex pathogeneses, but also may pinpoint potential targets for better diagnosis and treatment in complex diseases as MS.


Assuntos
Retrovirus Endógenos/genética , Desenvolvimento Fetal/genética , Regulação Viral da Expressão Gênica , Neoplasias/patologia , Doenças do Sistema Nervoso/patologia , Retrovirus Endógenos/patogenicidade , Epigênese Genética , Produtos do Gene env/fisiologia , Humanos , Imunidade/genética , Imunidade/imunologia , Neoplasias/genética , Neoplasias/imunologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/imunologia , Proteínas da Gravidez/fisiologia , Ativação Transcricional
8.
Nat Commun ; 12(1): 1135, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602924

RESUMO

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Mitocôndrias/genética , Mutação/genética , Doenças do Sistema Nervoso/genética , Transcrição Genética , Adolescente , Adulto , Criança , DNA Mitocondrial/genética , RNA Polimerases Dirigidas por DNA/química , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Lactente , Masculino , Doenças do Sistema Nervoso/patologia , Fosforilação Oxidativa , Linhagem , Domínios Proteicos , Subunidades Proteicas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
9.
Artigo em Inglês | MEDLINE | ID: mdl-33546463

RESUMO

BACKGROUND: Neuroinvasive properties of SARS-CoV-2 have allowed the hypothesis of several pathogenic mechanisms related to acute and chronic neurological sequelae. However, neuropathological correlates have been poorly systematically investigated, being retrieved from reports of single case or limited case series still. METHODS: A PubMed search was carried out to review all publications on autopsy in subjects with "COronaVIrus Disease-19" (COVID-19). Among them, we focused on histological findings of the brain, which were compared with those from the authors' autoptic studies performed in some COVID-19 patients. RESULTS: Only seven studies reported histological evidence of brain pathology in patients deceased for COVID-19, including three with reverse transcription-quantitative polymerase chain reaction evidence of viral infection. All these studies, in line with our experience, showed vascular-related and infection-related secondary inflammatory tissue damage due to an abnormal immune response. It is still unclear, however, whether these findings are the effect of a direct viral pathology or rather reflect a non-specific consequence of cardiovascular and pulmonary disease on the brain. CONCLUSIONS: Notwithstanding the limited evidence available and the heterogeneity of the studies, we provide a preliminary description of the relationship between SARS-CoV-2 and brain sequelae. Systematic autoptic investigations are needed for accurate detection and adequate management of these patients.


Assuntos
Encéfalo/patologia , Doenças do Sistema Nervoso/virologia , Autopsia , Humanos , Doenças do Sistema Nervoso/patologia
10.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537827

RESUMO

A major public health problem, traumatic brain injury (TBI) can cause severe neurological impairment. Although autophagy is closely associated with the pathogenesis of TBI, the role of autophagy in neurological deficits is unclear. The purpose of the present study was to investigate the molecular mechanisms of endoplasmic reticulum (ER) stress­induced autophagy and its detrimental effects on neurological outcomes following TBI. A rat model of TBI was established by controlled cortical impact. ER stress activation, autophagy induction and autophagic flux dysfunction were examined in the damaged hippocampus post­TBI. Pharmacological inhibition of ER stress significantly blocked post­traumatic autophagy activation, as evidenced by decreased conversion of microtubule­associated protein 1 light chain 3 (LC3)­I to LC3­II and Beclin­1 expression levels in the hippocampus region. Short hairpin RNA­mediated activating transcription factor 6 knockdown significantly prevented ER stress­mediated autophagy stimulation via targeting essential autophagic genes, including autophagy related (ATG)3, ATG9 and ATG12. Furthermore, neurological scores, foot fault test and Morris water maze were used to evaluate the neurological functions of TBI rats. The results revealed that the blockage of ER stress or autophagy attenuated TBI­induced traumatic damage and functional outcomes. In conclusion, these findings provided new insights into the molecular mechanisms of ER stress­induced autophagy and demonstrated its potential role in neurological deficiency following TBI.


Assuntos
Fator 6 Ativador da Transcrição/metabolismo , Autofagia , Lesões Encefálicas Traumáticas/metabolismo , Estresse do Retículo Endoplasmático , Doenças do Sistema Nervoso/metabolismo , Transdução de Sinais , Animais , Lesões Encefálicas Traumáticas/patologia , Masculino , Doenças do Sistema Nervoso/patologia , Ratos , Ratos Sprague-Dawley
11.
PLoS Genet ; 17(1): e1009224, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33417599

RESUMO

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer's Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer's disease, 6 genes with Parkinson's disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.


Assuntos
Doença de Alzheimer/genética , Descoberta de Drogas , Predisposição Genética para Doença , Transcriptoma/genética , Doença de Alzheimer/tratamento farmacológico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Terapia de Alvo Molecular , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/patologia
12.
Neurol Sci ; 42(4): 1255-1266, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33483885

RESUMO

BACKGROUND: Despite the expanding literature that discusses insights into the clinical picture and mechanisms by which the SARS-CoV-2 virus invades the nervous system, data on the neuropathologic findings of patients who died following SARS-CoV-2 infection is limited. METHODS: A broad literature search was done for published articles that reported on histopathological findings of the brain in patients with COVID-19 in PubMed by MEDLINE, Embase, CENTRAL by the Cochrane Library, and SCOPUS from December 31, 2019 to October 31, 2020. RESULTS: The systematic literature search strategy used resulted in a total of 1608 articles of which 14 were included in the analysis (PROSPERO registration number: CRD42020221022). There were ten case series, two case reports, one retrospective cohort, and one prospective cohort. The age of the patients ranged between 38 and 90 years old, most of them older than 65 years old (n=66, 45.2%) and males (n=79, 54.1%). Most tested negative in SARS-CoV-2 immunohistochemistry (n=70, 47.9%). The striking pathologic changes included diffuse edema (n=25, 17.1%), gliosis with diffuse activation of microglia and astrocytes (n=52, 35.6%), infarctions involving cortical and subcortical areas of the brain (n=4, 2.7%), intracranial bleed (subarachnoid hemorrhage and punctate hemorrhages) (n=18, 12.4%), arteriosclerosis (n=43, 29.5%), hypoxic-ischemic injury (n=41, 28.1%), and signs of inflammation (n=52, 35.6%). The cause of death was attributed to the cardiorespiratory system (n=66, 45.2%). CONCLUSIONS: The neuropathologic changes observed likely represent direct cytopathic effects and indirect effects secondary to host-specific inflammatory response induced by the viral infection. Further studies however are required to better elucidate the pathologic mechanism.


Assuntos
/patologia , Doenças do Sistema Nervoso/patologia , Sistema Nervoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inflamação/etiologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade
14.
BMC Neurol ; 21(1): 37, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504323

RESUMO

BACKGROUND: Manifestations of intractable hyponatremia and hypokalemia in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy have been rarely reported. CASE PRESENTATION: A 75-year-old male patient presented as the case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and intractable hypokalemia, showed fever, fatigue, and mental disorders. Signs and symptoms of meningoencephalitis, ataxia, and cognitive abnormalities. Magnetic resonance imaging (MRI) revealed multiple white matter lesions of the central nervous system. He had GFAP-IgG in the cerebrospinal fluid (CSF). After treatment with corticosteroids, his symptoms were alleviated gradually, and the level of electrolytes was normal. However, head contrast-enhanced MRI + susceptibility-weighted imaging (SWI) showed a wide afflicted region, and the serum GFAP-IgG turned positive. Considering the relapse of the disease, ha was treated with immunoglobulin and mycophenolate mofetil (MMF) to stabilize his condition. CONCLUSION: This case showed a rare disease with uncommon manifestations, suggesting that careful examination and timely diagnosis are essential for disease management and satisfactory prognosis.


Assuntos
Corticosteroides/uso terapêutico , Astrócitos/patologia , Proteína Glial Fibrilar Ácida/imunologia , Doenças do Sistema Nervoso/tratamento farmacológico , Idoso , Doenças Autoimunes/sangue , Doenças Autoimunes/líquido cefalorraquidiano , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/líquido cefalorraquidiano , Imagem por Ressonância Magnética , Masculino , Meningoencefalite/imunologia , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/patologia , Doenças Raras
15.
Arch Virol ; 166(3): 733-753, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33502593

RESUMO

The chronic dysfunction of neuronal cells, both central and peripheral, a characteristic of neurological disorders, may be caused by irreversible damage and cell death. In 2016, more than 276 million cases of neurological disorders were reported worldwide. Moreover, neurological disorders are the second leading cause of death. Generally, the etiology of neurological diseases is not fully understood. Recent studies have related the onset of neurological disorders to viral infections, which may cause neurological symptoms or lead to immune responses that trigger these pathological signs. Currently, this relationship is mostly based on epidemiological data on infections and seroprevalence of patients who present with neurological disorders. The number of studies aiming to elucidate the mechanism of action by which viral infections may directly or indirectly contribute to the development of neurological disorders has been increasing over the years but these studies are still scarce. Comprehending the pathogenesis of these diseases and exploring novel theories may favor the development of new strategies for diagnosis and therapy in the future. Therefore, the objective of the present study was to review the main pieces of evidence for the relationship between viral infection and neurological disorders such as Alzheimer's disease, Parkinson's disease, Guillain-Barré syndrome, multiple sclerosis, and epilepsy. Viruses belonging to the families Herpesviridae, Orthomyxoviridae, Flaviviridae, and Retroviridae have been reported to be involved in one or more of these conditions. Also, neurological symptoms and the future impact of infection with SARS-CoV-2, a member of the family Coronaviridae that is responsible for the COVID-19 pandemic that started in late 2019, are reported and discussed.


Assuntos
/patologia , Doenças do Sistema Nervoso/virologia , Tropismo Viral/fisiologia , Doença de Alzheimer/virologia , Epilepsia/virologia , Flaviviridae/metabolismo , Síndrome de Guillain-Barré/virologia , Herpesviridae/metabolismo , Humanos , Esclerose Múltipla/virologia , Doenças do Sistema Nervoso/patologia , Orthomyxoviridae/metabolismo , Doença de Parkinson/virologia , Retroviridae/metabolismo , /metabolismo
16.
J Neurosci ; 41(5): 845-854, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472820

RESUMO

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.


Assuntos
Interneurônios/metabolismo , Doenças do Sistema Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Agonistas GABAérgicos/farmacologia , Agonistas GABAérgicos/uso terapêutico , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/patologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia
17.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495808

RESUMO

The release of neurotransmitters following the fusion of synaptic vesicles and the presynaptic membrane is an important process in the transmission of neuronal information. Syntaxin-binding protein 1 (Munc18-1) is a synaptic fusion protein binding protein, which mainly regulates synaptic vesicle fusion and neurotransmitter release by interacting with soluble N-ethylmaleimide sensitive factor attachment protein receptor. In addition to affecting neurotransmitter transmission, Munc18-1 is also involved in regulating neurosynaptic plasticity, neurodevelopment and neuroendocrine cell release functions (including thyroxine and insulin release). A number of previous studies have demonstrated that Munc18-1 has diverse and vital biological functions, and that its abnormal expression serves an important role in the pathogenesis of a variety of neurological diseases, including epileptic encephalopathy, schizophrenia, autism, Parkinson's disease, Alzheimer's disease, multiple sclerosis, Duchenne's muscular dystrophy and neuronal ceroid lipofuscinosis. The present review summarizes the function of Munc18-1 and its possible relationship to the pathogenesis of various neurological diseases.


Assuntos
Proteínas Munc18/metabolismo , Doenças do Sistema Nervoso/metabolismo , Membranas Sinápticas/metabolismo , Transmissão Sináptica , Animais , Humanos , Fusão de Membrana , Proteínas Munc18/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Membranas Sinápticas/genética , Membranas Sinápticas/patologia
18.
RNA ; 27(4): 367-389, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33376192

RESUMO

RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.


Assuntos
Doenças Metabólicas/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA não Traduzido/genética , Apoptose/genética , Ciclo Celular/genética , Epigênese Genética , Marcadores Genéticos , Humanos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , RNA Mensageiro/metabolismo , RNA não Traduzido/metabolismo
19.
Methods Mol Biol ; 2187: 37-46, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32770500

RESUMO

The discovery of dynamic platforms in cell membranes, called lipid rafts or detergent resistant membrane domains, opened a new chapter on studies of membrane cell biology. Indeed, the analysis of lipid rafts enabled innovative ways to understand cellular and molecular mechanisms regulating normal and pathological processes. Lipid rafts have been studied in most cell types, where they work by providing transient and fluid architectural scaffolding platforms regulating a spectrum of important signaling pathways, including receptor activities, protein-protein interactions, posttranslational modifications of proteins and lipids and the function of ion channels. In this chapter, we will explain how to isolate these membrane domains from neural tissue samples and perform further analysis of proteins and lipids.


Assuntos
Lipídeos de Membrana/metabolismo , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/patologia , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Animais , Membrana Celular/metabolismo , Membrana Celular/patologia , Canais Iônicos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Mapas de Interação de Proteínas/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Transdução de Sinais/fisiologia
20.
Cytokine ; 138: 155404, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33360025

RESUMO

The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger a hyperinflammatory state characterized by elevated cytokine levels known as hypercytokinemia or cytokine storm, observed most often in severe patients. Though COVID-19 is known to be a primarily respiratory disease, neurological complications affecting both the central and peripheral nervous systems have also been reported. This review discusses potential routes of SARS-CoV-2 neuroinvasion and pathogenesis, summarizes reported neurological sequelae of COVID-19, and examines how aberrant cytokine levels may precipitate these complications. Clarification of the pathogenic mechanisms of SARS-CoV-2 is needed to encourage prompt diagnosis and optimized care. In particular, identifying the presence of cytokine storm in patients with neurological COVID-19 manifestations will facilitate avenues for treatment. Future investigations into aberrant cytokine levels in COVID-19 patients with neurological symptoms as well as the efficacy of cytokine storm-targeting treatments will be critical in elucidating the pathogenic mechanisms and effective treatments of COVID-19.


Assuntos
/patologia , Transtornos Cerebrovasculares/patologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Doenças do Sistema Nervoso/patologia , /terapia , Sistema Nervoso Central/patologia , Transtornos Cerebrovasculares/virologia , Síndrome da Liberação de Citocina/terapia , Humanos , Doenças do Sistema Nervoso/virologia , Sistema Nervoso Periférico/patologia
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