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Astrocytes, a major class of glial cells, are an important element at the synapse where they engage in bidirectional crosstalk with neurons to regulate numerous aspects of neurotransmission, circuit function, and behavior. Mutations in synapse-related genes expressed in both neurons and astrocytes are central factors in a vast number of neurological disorders, making the proteins that they encode prominent targets for therapeutic intervention. Yet, while the roles of many of these synaptic proteins in neurons are well established, the functions of the same proteins in astrocytes are largely unknown. This gap in knowledge must be addressed to refine therapeutic approaches. In this chapter, we integrate multiomic meta-analysis and a comprehensive overview of current literature to show that astrocytes express an astounding number of genes that overlap with the neuronal and synaptic transcriptomes. Further, we highlight recent reports that characterize the expression patterns and potential novel roles of these genes in astrocytes in both physiological and pathological conditions, underscoring the importance of considering both cell types when investigating the function and regulation of synaptic proteins.
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Astrócitos , Neurônios , Sinapses , Astrócitos/metabolismo , Sinapses/metabolismo , Humanos , Neurônios/metabolismo , Animais , Expressão Gênica , Transmissão Sináptica , TranscriptomaRESUMO
Benign epithelial skin cysts containing multiple components of the folliculo-sebaceous apocrine unit are only rarely reported in the literature. Here, we describe a 12-year-old girl who presented with a cystic mass on the vertex of her scalp. Upon resection, it showed a hybrid benign skin cyst with interesting histological features of both pilar and apocrine differentiation. The clinicopathological and imaging findings of this unusual skin cyst, successfully managed by a plastic surgeon and neurosurgeon, are described. Pathologists and clinicians should be aware of this type of skin cyst rarely encountered in their clinical practice.
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A 48-year-old woman was referred with an 18-year history of focal-onset seizures. She also reported years-long slowly progressive right-sided weakness that was corroborated on examination. Repeated brain MRIs over 15 years showed multifocal left hemispheric T2 fluid-attenuated inversion recovery-hyperintense lesions with patchy enhancement and microhemorrhages, no diffusion restriction, and a left cerebellar infarct (Figure 1, A-F). Only 2 nonspecific white matter lesions were seen contralaterally, indicating largely unihemispheric disease. Differential diagnosis included unilateral primary angiitis of the CNS (PACNS), Rasmussen encephalitis, and myelin oligodendrocyte glycoprotein antibody-associated disease.1 Serum and CSF testing for autoimmune, infectious, and malignant etiologies and whole-body fluorodeoxyglucose-PET, whole-exome genetic sequencing, and MR vessel-wall imaging were nondiagnostic. Brain biopsy revealed vasculitis (Figure 2, A-F), and the patient was diagnosed with unilateral PACNS. Treatment with mycophenolate mofetil has been initiated. Unilateral PACNS is a rare unihemispheric disease characterized by an indolent course and seizures, recognition of which is critical to accurate diagnosis.1,2.
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Encefalite , Vasculite do Sistema Nervoso Central , Feminino , Humanos , Pessoa de Meia-Idade , Vasculite do Sistema Nervoso Central/diagnóstico por imagem , Vasculite do Sistema Nervoso Central/tratamento farmacológico , Imageamento por Ressonância Magnética , Encefalite/complicações , Convulsões/complicaçõesRESUMO
Visual impairments in albinism result from decreased ipsilateral retinal projections. In this issue of Neuron, Slavi, Balasubramanian, and colleagues1 demonstrate how low CyclinD2 in the ciliary marginal zone perturbs generation of ipsilaterally projecting RGCs and that restoring CyclinD2 improves vision in albino mice.
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Albinismo , Células Ganglionares da Retina , Animais , Camundongos , Retina , Visão Ocular , Vias VisuaisRESUMO
Background: Chikungunya virus (CHIKV) is a mosquito-borne pathogen, within the Alphavirus genus of the Togaviridae family, that causes ~1.1 million human infections annually. CHIKV uses Aedes albopictus and Aedes aegypti mosquitoes as insect vectors. Human infections can develop arthralgia and myalgia, which results in debilitating pain for weeks, months, and even years after acute infection. No therapeutic treatments or vaccines currently exist for many alphaviruses, including CHIKV. Targeting the phagocytosis of CHIKV by macrophages after mosquito transmission plays an important role in early productive viral infection in humans, and could reduce viral replication and/or symptoms. Methods: To better characterize the transcriptional response of macrophages during early infection, we generated RNA-sequencing data from a CHIKV-infected human macrophage cell line at eight or 24 hours post-infection (hpi), together with mock-infected controls. We then calculated differential gene expression, enriched functional annotations, modulated intracellular signaling pathways, and predicted therapeutic drugs from these sequencing data. Results: We observed 234 pathways were significantly affected 24 hpi, resulting in six potential pharmaceutical treatments to modulate the affected pathways. A subset of significant pathways at 24 hpi includes AGE-RAGE, Fc epsilon RI, Chronic myeloid leukemia, Fc gamma R-mediated phagocytosis, and Ras signaling. We found that the MAPK1 and MAPK3 proteins are shared among this subset of pathways and that Telmisartan and Dasatinib are strong candidates for repurposed small molecule therapeutics that target human processes. The results of our analysis can be further characterized in the wet lab to contribute to the development of host-based prophylactics and therapeutics.
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Aedes , Febre de Chikungunya , Vírus Chikungunya , Animais , Humanos , Vírus Chikungunya/genética , Mosquitos Vetores , Febre de Chikungunya/tratamento farmacológico , Linhagem Celular , MacrófagosRESUMO
OBJECTIVES: To identify the epitope on α-synuclein (α-syn) to which antibodies against the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) bind and to determine whether antibodies targeting this mimicry domain are present in human sera. METHODS: Reactivity of the α-syn-cross-reacting anti-LMP1 monoclonal antibody CS1-4 to a synthetic peptide containing the putative mimicry domain was compared to those in which this domain was mutated and to murine and rat α-syn (which differ from human α-syn at this site) in Western blots. Using ELISA, sera from EBV+ (n = 4) and EBV- (n = 12) donors as well as those with infectious mononucleosis (IM; n = 120), and Hodgkin disease (HD; n = 33) were interrogated for antibody reactivity to synthetic peptides corresponding to regions of α-syn and LMP1 containing the mimicry domain. RESULTS: CS1-4 showed strong reactivity to wild-type human α-syn, but not to the mutant peptides or rodent α-syn. Control EBV- and EBV+ sera showed no reactivity to α-syn or LMP1 peptides. However, a significant proportion of IM and HD sera contained immunoglobulin M (IgM) (59% and 70%, in IM and HD, respectively), immunoglobulin G (IgG) (40% and 48%), and immunoglobulin A (IgA) (28% and 36%) antibodies to both peptides, as well as a significant correlation in the titers of IgM (ρ = 0.606 and 0.664, for IM and HD, respectively), IgG (0.526 and 0.836), and IgA (0.569 and 0.728) antibodies targeting LMP1 and α-syn peptides. CONCLUSIONS: Anti-EBV-LMP1 antibodies cross-reacting with a defined epitope in α-syn are present in human patients. These findings may have implications for the pathogenesis of synucleinopathies.
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In vivo studies have shown that blood-brain barrier (BBB) dysfunction is involved in the course of Parkinson's disease (PD). However, these have lacked either anatomic definition or the ability to recognize minute changes in BBB integrity. Here, using histologic markers of serum protein, iron, and erythrocyte extravasation, we have shown significantly increased permeability of the BBB in the postcommissural putamen of PD patients. The dense innervation of the striatum by PD-affected regions allows for exploitation of this permeability for therapeutic goals. These results are also discussed in the context of the retrograde trans-synaptic hypothesis of PD spread.
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Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Permeabilidade Capilar , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Eritrócitos/metabolismo , Eritrócitos/patologia , Feminino , Humanos , Ferro/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
UCHL1 (ubiquitin carboxyterminal hydrolase 1) is a deubiquitinating enzyme that is particularly abundant in neurons. From studies of a spontaneous mutation arising in a mouse line it is clear that loss of function of UCHL1 generates profound degenerative changes in the central nervous system, and it is likely that a proteolytic deficit contributes to the pathology. Here these effects were found to be recapitulated in mice in which the Uchl1 gene had been inactivated by homologous recombination. In addition to the previously documented neuropathology associated with loss of UCHL1 function, axonal swellings were detected in the striatum. In agreement with previously reported findings the loss of UCHL1 function was accompanied by perturbations in ubiquitin pools, but glutathione levels were also significantly depleted in the brains of the knockout mice, suggesting that oxidative defense mechanisms may be doubly compromised. To determine if, in addition to its role in the central nervous system, UCHL1 function is also required for homeostasis of the enteric nervous system the gastrointestinal tract was analyzed in UCHL1 knockout mice. The mice displayed functional changes and morphological changes in gut neurons that preceded degenerative changes in the brain. The changes were qualitatively and quantitatively similar to those observed in wild type mice of much greater age, and strongly resemble changes reported for elderly humans. UCHL1 knockout mice should therefore serve as a useful model of gut aging.
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Current concepts regarding the pathogenesis of Parkinson's disease support a model whereby environmental factors conspire with a permissive genetic background to initiate the disease. The identity of the responsible environmental trigger has remained elusive. There is incontrovertible evidence that aggregation of the neuronal protein alpha-synuclein is central to disease pathogenesis. A novel hypothesis of Parkinson's pathogenesis, articulated by Braak and colleagues, implicates a pathogen acting in the olfactory mucosa and gastrointestinal tract as the inciting agent. In this point-of-view article, we hypothesize that α-synuclein aggregation in Parkinson's disease is an Epstein-Barr virus (EBV)-induced autoimmune phenomenon. Specifically, we have shown evidence for molecular mimicry between the C-terminal region of α-synuclein and a repeat region in the latent membrane protein 1 encoded by EBV. We hypothesize that, in genetically-susceptible individuals, anti-EBV latent membrane protein antibodies targeting the critical repeat region cross react with the homologous epitope on α-synuclein and induce its oligomerization. Consistent with the Braak's proposed pattern of spread, we contend that axon terminals in the lamina propria of the gut are among the initial targets, with subsequent spread of pathology to the CNS. While at this time, we can only provide evidence from the literature and preliminary findings from our own laboratory, we hope that our hypothesis will stimulate the development of tractable experimental systems that can be exploited to test it. Further support for an EBV-induced immune pathogenesis for Parkinson's disease could have profound therapeutic implications.
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Herpesvirus Humano 4/fisiologia , Mimetismo Molecular/fisiologia , Doença de Parkinson/genética , Doença de Parkinson/virologia , Sequência de Aminoácidos , Animais , Humanos , Dados de Sequência MolecularRESUMO
Parkinson's disease is characterized by the pathological aggregation of Alpha-synuclein. The dual-hit hypothesis proposed by Braak implicates the enteric nervous system as an initial site of α-synuclein aggregation with subsequent spread to the central nervous system. Regional variations in the spatial pattern or levels of α-synuclein along the enteric nervous system could have implications for identifying sites of onset of this pathogenic cascade. We performed immunohistochemical staining for α-synuclein on gastrointestinal tissue from patients with no history of neurological disease using the established LB509 antibody and a new clone, MJFR1, characterized for immunohistochemistry here. We demonstrate that the vermiform appendix is particularly enriched in α-synuclein-containing axonal varicosities, concentrated in its mucosal plexus rather than the classical submucosal and myenteric plexuses. Unexpectedly, intralysosomal accumulations of α-synuclein were detected within mucosal macrophages of the appendix. The abundance and accumulation of α-synuclein in the vermiform appendix implicate it as a candidate anatomical locus for the initiation of enteric α-synuclein aggregation and permits the generation of testable hypotheses for Parkinson's disease pathogenesis.
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Mucosa Gástrica/metabolismo , Trato Gastrointestinal/metabolismo , alfa-Sinucleína/análise , alfa-Sinucleína/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Humanos , Macrófagos/metabolismo , Pessoa de Meia-Idade , Fibras Nervosas/metabolismo , Sinaptofisina/metabolismo , Ubiquitina Tiolesterase/metabolismo , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
OBJECTIVES: Insulin exposure after inhalation has been reported to be altered significantly in subjects with chronic obstructive pulmonary disease (COPD). In this study, the rate and extent of insulin exposure was compared in healthy volunteers and subjects with COPD following administration of Technosphere * Insulin (TI), a dry powder insulin formulation for pulmonary delivery. METHODS: Insulin pharmacokinetics were evaluated in an open-label, single-dose, hyperinsulinemic-euglycemic glucose clamp study in 19 nondiabetic, nonsmoking healthy subjects (mean age [±SD] = 50.9 ± 14.1 years, body mass index = 29.1 ± 3.5 kg/m(2), forced expiratory volume in 1 second (FEV(1)) = 3.52 ± 1.02 L) and 17 nondiabetic subjects with mild-to-moderate COPD (mean age = 60.0 ± 9.0 years, body mass index = 28.5 ± 5 kg/m(2), FEV(1) = 2.56 ± 0.83 L). Subjects received a single 30-U dose of TI. Serial blood samples were obtained for insulin and C-peptide determination through 480 min after dosing. Insulin concentrations were adjusted for endogenous insulin by C-peptide correction; pharmacokinetic parameters were estimated using the corrected values. RESULTS: For the COPD and non-COPD groups, respectively, mean peak insulin (C(max)) was 34.7 µU/mL and 39.5 µU/mL (p = 0.29), median t(max) was 15 and 12 min (p = 0.24), and mean insulin exposure from time 0 to 240 min (AUC(0-240)) was 2037 µU/mL · min and 2279 µU/mL · min (p = 0.47). Cough was the most common respiratory adverse event observed. One instance of hypoglycemia was reported and was attributed to trial procedure. CONCLUSIONS: The rapid insulin absorption and the resulting insulin pharmacokinetic profile following TI inhalation were not significantly altered in the mild-to-moderate COPD population studied; however, long-term safety and efficacy of TI have not been established in patients with mild or moderate COPD. Longer-term experience is needed to fully characterize the effects of COPD on insulin PK following TI administration.