关键词： Immunology   Rodent models   Lipids   Peptides and proteins   Central nervous system  

摘要： Lysophosphatidylserine (lyso-PS), a lysophospholipid derived from phosphatidylserine (PS), has emerged as a potent signaling lipid in mammalian physiology. In vivo, the metabolic serine hydrolases ABHD16A and ABHD12 are major lipases that biosynthesize and degrade lyso-PS, respectively. Of biomedical relevance, deleterious mutations to ABHD12 cause accumulation of lyso-PS in the brain, and this deregulated lyso-PS metabolism leads to the human genetic neurological disorder PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). While the roles of ABHD16A and ABHD12 in lyso-PS metabolism in the mammalian brain are well established, the anatomical and (sub)cellular localizations of both lipases and the functional cross-talk between them with respect to regulating lyso-PS lipids remain under investigated. Here, using subcellular organelle fractionation, biochemical assays, and immunofluorescence-based high-resolution microscopy, we show that the PS lipase ABHD16A is an endoplasmic reticulum-localized enzyme, an organelle intricately regulating cellular PS levels. In addition, leveraging immunohistochemical analysis using genetic ABHD16A and ABHD12 knockout mice as important controls, we map the anatomical distribution of both of these lipases in tandem in the murine brain and show for the first time the distinct localization of these lipases to different regions and cells of the cerebellum. We complement the aforementioned immunohistochemical studies by quantitatively measuring lyso-PS concentrations in various brain regions using mass spectrometry and find that the cerebellar lyso-PS levels are most affected by deletion of ABHD16A (decreased) or ABHD12 (increased). Taken together, our studies provide new insights into lyso-PS signaling in the cerebellum, the most atrophic brain region in human PHARC subjects.

关键词： mitochondria   retrograde signalling   disease   neuron   Parkinson's   Alzheimer's  

摘要： Neuronal mitochondrial dysfunction causes primary mitochondrial diseases and likely contributes to neurodegenerative diseases including Parkinson's and Alzheimer's disease. Mitochondrial dysfunction has also been documented in neurodevelopmental disorders such as tuberous sclerosis complex and autism spectrum disorder. Only symptomatic treatments exist for neurodevelopmental disorders, while neurodegenerative diseases are largely untreatable. Altered mitochondrial function activates mitochondrial retrograde signalling pathways, which enable signalling to the nucleus to reprogramme nuclear gene expression. In this review, we discuss the role of mitochondrial retrograde signalling in neurological diseases. We summarize how mitochondrial dysfunction contributes to neurodegenerative disease and neurodevelopmental disorders. Mitochondrial signalling mechanisms that have relevance to neurological disease are discussed. We then describe studies documenting retrograde signalling pathways in neurons and glia, and in animal models of neuronal mitochondrial dysfunction and neurological disease. Finally, we suggest how specific retrograde signalling pathways can be targeted to develop novel treatments for neurological diseases. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.

关键词： CAPS   TRAPS   FMF   Multiple sclerosis   Autoinflammation   Autoimmunity  

摘要： Background Neurological manifestations and the co-occurrence of multiple sclerosis (MS) have been reported in patients with autoinflammatory diseases (AID) and variants of theNLRP3-,MEFV-, orTNFRSF1Agene. However, type and frequency of neurological involvement are widely undetermined. Methods We assessed clinical characteristics of 151 (108 with MS) patients carrying NLRP3-, MEFV- and TNFRSF1A low-penetrance variants from the Institute of Clinical Neuroimmunology. We evaluated demographic, genetic, and clinical features with a focus on central nervous system (CNS) involvement including magnetic resonance imaging (MRI) results and cerebrospinal fluid (CSF) data. The disease course of AID patients with MS was compared to a matched MS control group without mutations. Results The genetic distribution comprised 36 patients (23%) with NLRP3- and 66 patients (43%) with TNFRSF1A low-penetrance variants as well as 53 (34%) patients carrying pathogenic mutations or low-penetrance variants in theMEFVgene. MS patients displayed most frequently the R92Q TNFRSF1A variant (n= 51;46%) followed by the Q703K NLRP3 variant (n= 15;14%) and the E148Q substitution (n= 9;8%) in the MEFV gene. The disease course of MS was not influenced by the genetic variants and did not differ from MS patients (n= 51) without mutations. AID patients without MS most frequently harbored MEFV mutations (n= 19, 43%) followed by NLRP3- (n= 17, 39%) and TNFRSF1A (n= 8, 18%) low-penetrance variants. Sixteen (36%) of them suffered from severe CNS involvement predominantly recurrent aseptic meningoencephalitis and optic neuritis accompanied by abnormal MRI and CSF results. Severe CNS inflammation was associated with the Q703K allele. Headache was a highly prevalent neurological symptom (up to 74%), irrespective of the underlying genetic variation. The NLRP3 cohort without MS more frequently exhibited affections of the cranial nerves (CN) (p=0.0228) and motor symptoms (p=0.0455). Elevated acute-phase reactants wer

关键词： COVID-19   SARS-CoV-2   healthcare in COVID-19   anosmia   ACE2   neurovirulence SARS-CoV-2  

摘要： The 2019 novel coronavirus disease (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a zoonotic disease that is dominated by pulmonary symptoms. However, recent reports of isolation of the virus from cerebrospinal fluid (CSF) coupled with radiological evidence of zones of necrosis in the brain, have elucidated the neurotropic potential of SARS-CoV-2. The acute respiratory failure seen in patients with COVID-19 is alarming and could be due to the effects of SARS-CoV-2 on the central respiratory regulatory centers in the brainstem. Appropriate interventions can be implemented to prevent severe outcomes of neurological invasion by SARS-CoV-2 to reduce the morbidity and mortality of patients with COVID19. It is of paramount importance that the scientific community alerts the healthcare professionals of the pieces of evidence that can herald them on the covert neurological deficits in progress in COVID-19.

关键词： IL-4   microglia/macrophages   polarization   JAK1/STAT6   ICH  

摘要： Inflammatory damage following ICH is often attributed to microglia/macrophage activation. In many diseases, IL-4 has been proven to switch microglia/macrophages from the pro-inflammatory to the antiinflammatory subtype. However, the role and underlying mechanism of IL-4 in ICH, especially in neuroprotection, remain unknown. In our study, we constructed a microglia/macrophage polarization model in BV2 cells to verify that the M2 shift of microglia/macrophages was mediated by JAK1/STAT6 after IL-4 treatment and then revealed that in vitro administration of IL-4 decreased M1 markers, pro-inflammatory cytokines and neuroapoptosis markers but significantly increased M2 markers and anti-inflammatory cytokines. Using an ICH model in mice, we observed that IL-4 administration decreased neurological deficits, brain edema and infarct lesions induced by ICH. We verified that IL-4 mediates inflammation by regulating M1/M2 polarization in ICH and explored the underlying mechanism. Furthermore, we discovered that pathway components and apoptosis-related proteins showed consistent trends based on their respective roles, and inferred that the process that TNF-activates caspase-3 may be the crosstalk that microglia phagocytosis developed into accelerate apoptosis of cells in ICH. In conclusion, our study demonstrates that IL-4 may promote M2 microglia/macrophage polarization partly through the JAK1/STAT6 pathway to alleviate neuroinflammation after ICH. (C) 2020 Published by Elsevier Ltd on behalf of IBRO.

关键词： GAD65   Autoantibodies   Neurological disorders   Genetic variants  

摘要： Objective: In patients with GAD-antibody (ab) associated neurological disorders coexistence of other autoimmune disorders is observed. Methods: In this exploratory study we analysed variations in 33 candidate genes involved in autoimmunity or representing immunological check-points using next-generation sequencing. We performed haplotype-analysis of HLA-DRB1 and HLA-DQB1. Additionally, we analysed levels of sFasL, IL10, and IL18 in serum of patients and healthy controls. Results: 19 patients (3 males, 16 females;mean age at onset: 46.4 years) with positive GAD-ab and the following neurological phenotypes were included: n = 8 cerebellar ataxia, n = 6 limbic encephalitis, n = 4 stiff person syndrome, n = 1 demyelinating CNS disease with recurrent optic neuritis. 15 patients exhibited at least one other autoimmune disorder and/or showed other auto-ab. We identified several variations in genes linked to autoimmunity or representing check-point proteins. Most frequently (14/19 patients, allele frequency: 42.1%), we observed an amino acid exchange in the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene. Two of the observed variants are known to cause alterations of protein function (Y446C in caspase-10, K750N in proteintyrosin-phosphatase, non-receptor type 22). These latter variants were detected in two related patients (mother and daughter) who both present with GAD-ab-associated neurological disorders but with different clinical phenotypes. The rare haplotype DRB1*15:01:01 similar to DQA1*01:02:01 similar to DQB1*05:02:01 previously described in patients with GAD-ab-associated neurological disorders was not observed in any of our patients. No elevated serum levels of sFasL, IL18 or IL10 were observed in patients indicating no typical phenotype of autoimmune lymphoproliferate syndrome. Conclusions: These findings suggest genetic risk factors in patients with GAD-ab-associated neurological disorders.

关键词： Eslicarbazepine acetate   Adverse effects   Safety profile  

摘要： Objectives: This study aimed to assess the tolerability and safety profile of eslicarbazepine acetate (ESL). Methods: Placebo controlled, double-blind randomized controlled trials (RCTs) were enrolled by searching Pubmed, Embase, Cochrane Online Library, and ***. Studies evaluating the safety of ESL on any neurological disorders were included. Adverse events (AEs), serious AEs and AEs-related withdrawals were pooled by direct or indirect meta-analysis. Results: A total of 4067 patients in 13 RCTs (5 for refractory partial epilepsy, 2 for bipolar I disorder, 1 for migraine, 1 for fibromyalgia, 2 for diabetic neuropathic pain, and 2 for post-herpetic neuralgia) were included. Meta-analysis revealed that ESL treatment had a higher incidence of serious AEs and AEs-related withdrawals than the placebo. Of 35 reported AEs, 13 were significantly associated with ESL treatment, including blurred vision, diplopia, vertigo, nausea, vomiting, fatigue, dizziness, somnolence, headache, rash, hyponatraemia, increased gamma-glutamyl transferase, and dysarthria. Subgroup analysis revealed that dizziness was the only AE significant at 400 mg/day, while diplopia, nausea, vomiting, dizziness, somnolence, rash, and hyponatremia at 800 mg/day, and blurred vision, diplopia, vertigo, nausea, vomiting, fatigue, dizziness, somnolence, headache, rash, and hyponatremia at 1200 mg/day were significant. Adjunctive use of ESL in refractory epilepsy significantly led to higher risk for vestibulocerebellar AEs than other disorders. Conclusions: ESL treatment was related to a range of AEs, especially at high doses or when used as adjunctive therapy in epilepsy. While the majority of AEs of ESL were related to the vestibulocerebellar system, hyponatremia and rash should also be noted by clinicians.

关键词： Chronic granulomatous disease   Systemic lupus erythematosus   Autoimmunity   CNS vasculitis  

摘要： Chronic granulomatous disease (CGD) is an uncommon genetic immunodeficiency disorder affecting neutrophil function, characterized by recurrent bacterial and fungal infections. X-linked carriers of CGD have an increased risk of autoimmune disorders, in particular lupus like disorders. We describe the case of a 37 years old female carrier of X-linked CGD, who presented with clinical features and serology consistent with a definite diagnosis of Systemic lupus erythematosus (SLE), with rare immune mediated neurological manifestations including secondary central nervous system (CNS) vasculitis and Longitudinally extensive transverse myelitis (LETM), responsive to immunomodulation. These neurological manifestations have not been described previously in carriers of CGD. We recommend early diagnosis of these immune mechanisms, especially in X-linked carriers of CGD, and appropriate immunomodulation in order to improve life expectancy and improve neurological outcome.

关键词： miR-142-5p   Isoflurane   Neurological impairment   Viability   Apoptosis  

摘要： Background Isoflurane can lead to neuron damage to the developing brain, resulting in learning and memory disability. The aim of this study was to investigate the role of miR-142-5p on isoflurane-induced neurological impairment. Methods The Morris water maze (MWM) test was performed to evaluate spatial learning and memory of rats. The expression level of miR-142-5p was measured using qRT-PCR. MTT assay was used to calculate the viability of hippocampal neuronal cells. The cell apoptosis was analyzed using Flow cytometric assay. Results Isoflurane treatment led to the increase of neurological function score and escape latency, and the reduction of time spent in the original quadrant in rats. The expression level of miR-142-5p was increased significantly in isoflurane-treated rats. MiR-142-5p downregulation protected against isoflurane-induced neurological impairment, which was reflected by the decrease of neurological function score and escape latency, and the increase of time spent in the original quadrant. In vitro, downregulation of miR-142-5p alleviated isoflurane-induced neuron cell viability inhibition, and relieved isoflurane-induced cell apoptosis. Conclusions MiR-142-5p downregulation plays a neuroprotective role in protecting against isoflurane-induced neurological impairment through regulating neuron cell viability and apoptosis. It provides a theoretical basis for the investigation of the mechanism underlying the effect on isoflurane-induced neurological impairment.

关键词： Neurological disorders   motor impairment   communication   leisure   smartphone   tablet  

摘要： Objective To assess a simple technology solution to support basic communication and leisure in people with neurological disorders, extensive motor impairment, and absence of speech. Design The design was a non-concurrent multiple baseline across participants. Methods The study included eight participants and assessed a technology setup including a Samsung Galaxy Tab S2 LTE tablet and a Samsung Galaxy A3 smartphone. The smartphone, automated via MacroDroid, presented the participant with leisure, messages, and caregiver options. Choosing leisure or messages (by activating the smartphone's proximity sensor) led the smartphone to present the alternatives available for that option and eventually verbalize the alternative selected. This verbalization triggered the tablet's Google Assistant and led the tablet to present a leisure event or start a message exchange. Choosing the caregiver led the smartphone to invite the caregiver to interact with the participant. Results During baseline (i.e., when a standard smartphone was available), the participants did not activate any of the options. During intervention and post-intervention (i.e., with the technology described above), participants activated all options and spent most of the session time positively engaged with them. Conclusions The aforementioned technology seems to be a useful tool for individuals like those involved in this study.