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Epilepsy is a severe, relapsing, and multifactorial neurological disorder. Studies regarding the accurate diagnosis, prognosis, and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy. The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression, protein expression, ion channel activity, energy metabolites, and gut microbiota composition. Satisfactory results are lacking for conventional treatments for epilepsy. Surgical resection of lesions, drug therapy, and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy. Non-pharmacological treatments, such as a ketogenic diet, gene therapy for nerve regeneration, and neural regulation, are currently areas of research focus. This review provides a comprehensive overview of the pathogenesis, diagnostic methods, and treatments of epilepsy. It also elaborates on the theoretical basis, treatment modes, and effects of invasive nerve stimulation in neurotherapy, including percutaneous vagus nerve stimulation, deep brain electrical stimulation, repetitive nerve electrical stimulation, in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation. Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures. Additionally, many new technologies for the diagnosis and treatment of epilepsy are being explored. However, current research is mainly focused on analyzing patients' clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level, which has led to a lack of consensus regarding the mechanisms related to the disease.
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Mutations in the γ-amino butyric acid type A (GABAA) receptor γ2 subunit gene, GABRG2, have been associated with refractory epilepsy. Increasing evidence indicates that suberoylanilide hydroxamic acid (SAHA), a broad-spectrum histone acetyltransferases (HDACs) inhibitor, can inhibit seizure onset. However, the mechanisms involved remains unknown. The present study aimed to explore the anti-epileptic effect and underlying mechanisms of SAHA in the treatment of refractory epilepsy induced by GABRG2 mutation. In the zebrafish line expressing human mutant GABRG2(F343L), Tg(hGABRG2F343L), SAHA was found to reduce seizure onset, swimming activity, and neuronal activity. In both Tg(hGABRG2F343L) zebrafish and HEK293T cells transfected with GABAA receptor subunits, SAHA could improve the pan-acetylation level and reduce the expression of HDAC1/10. The decreased expressions of GABAA receptor subunits could be rescued by SAHA treatment both in vivo and in vitro, which might be the result of increased gene transcription and protein trafficking. The up-regulated acetylation of histone H3 and H4 as well as Bip expression might be involved in the process. Taken together, our data proved that both histone and non-histone acetylation might contribute to the anti-epileptic effect of SAHA in refractory epilepsy caused by GABRG2(F343L) mutation, demonstrating SAHA as a promising therapeutic agent for refractory epilepsy.
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Mutação , Receptores de GABA-A , Vorinostat , Peixe-Zebra , Animais , Humanos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Células HEK293 , Vorinostat/farmacologia , Vorinostat/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/genética , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Animais Geneticamente ModificadosRESUMO
OBJECTIVE: To explore the mechanism involved in variable phenotypes of epilepsy models induced by γ-aminobutyric acid type A γ2 subunit (GABRG2) mutations. METHODS: The zebrafish carrying wild-type (WT) GABRG2, mutant GABRG2(P282S), GABRG2(F343L) and GABRG2(I107T) were established by Tol2kit transgenesis system and Gateway method. Behavioral analysis of different transgenic zebrafish was performed with the DanioVision Video-Track framework and the brain activity was analyzed by field potential recording with MD3000 Bio-signal Acquisition and Processing System. The transcriptome analysis was applied to detect the underlying mechanisms of variable phenotypes caused by different GABRG2 mutations. RESULTS: The established Tg(hGABRG2P282S ) zebrafish showed hyperactivity and spontaneous seizures, which were more sensitive to chemical and physical epileptic stimulations. Traditional antiepileptic drugs, such as Clonazepam (CBZ) and valproic acid (VPA), could ameliorate the hyperactivity in Tg(hGABRG2P282S ) zebrafish. The metabolic pathway was significantly changed in the brain transcriptome of Tg(hGABRG2P282S ) zebrafish. In addition, the behavioral activity, production of pro-inflammatory factors, and activation of the IL-2 receptor signal pathway varied among the three mutant zebrafish lines. CONCLUSION: We successfully established transgenic zebrafish epileptic models expressing human mutant GABRG2(P282S), in which CBZ and VPA showed antiepileptic effects. Differential inflammatory responses, especially the SOCS/JAK/STAT signaling pathway, might be related to the phenotypes of genetic epilepsy induced by GABRG2 mutations. Further study will expand the pathological mechanisms of genetic epilepsies and provide a theoretical basis for searching for effective drug treatment.
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Epilepsia , Peixe-Zebra , Animais , Humanos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Epilepsia/genética , Mutação/genética , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico , Fenótipo , Inflamação/genéticaRESUMO
Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease, accompanied by the gradual loss of motor neuron, even life-threatening. However, the pathogenesis, early diagnosis, and effective strategies of ALS are not yet completely understood. In this study, the function of differentially expressed genes (DEGs) in non-neuronal cells of the primary motor cortex of ALS patients (DATA1), the brainstem of SOD1 mutant ALS mice (DATA2), and the whole blood tissue of ALS patients (DATA3) were explored. The results showed that the functions of DEGs in non-neuronal cells were mainly related to energy metabolism (such as oxidative phosphorylation) and protein synthesis. In non-neuronal cells, six upregulated DEGs (HSPA8, SOD1, CALM1, CALM2, NEFL, COX6C) and three downregulated DEGs (SNRNP70, HSPA1A, HSPA1B) might be key factors in regulating ALS. Microglia played a key role in the development of ALS. The expression of SOD1 and TUBA4A in microglia in DATA1 was significantly increased. The integration analysis of DEGs in DATA1 and DATA2 showed that SOD1 and CALM1 might be potential biomarkers. The integration analysis of DEGs in DATA1 and DATA3 showed that CALM2 and HSPA1A might be potential biomarkers. Cell interaction showed that the interaction between microglia and other cells was reduced in high oxidative phosphorylation states, which might be a risk factor in ALS. Our research provided evidence for the pathogenesis, early diagnosis, and potential targeted therapy for ALS.
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Esclerose Lateral Amiotrófica , Biomarcadores , Metabolismo Energético , Microglia , Análise de Célula Única , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Microglia/metabolismo , Microglia/patologia , Animais , Metabolismo Energético/genética , Humanos , Biomarcadores/metabolismo , Análise de Sequência de RNA/métodos , Camundongos , Camundongos Transgênicos , Masculino , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , FemininoRESUMO
JOURNAL/nrgr/04.03/01300535-202408000-00039/figure1/v/2023-12-16T180322Z/r/image-tiff Biomarkers are required for the early detection, prognosis prediction, and monitoring of amyotrophic lateral sclerosis, a progressive disease. Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarkers. In this study, we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral sclerosis compared with five healthy controls. Substantial upregulation of serum proteins related to multiple functional clusters was observed in patients with sporadic amyotrophic lateral sclerosis. Potential biomarkers were selected based on functionality and expression specificity. To validate the proteomics profiles, blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay. Eight substantially upregulated serum proteins in patients with sporadic amyotrophic lateral sclerosis were selected, of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls (area under the curve [AUC] = 0.713, P < 0.0001). To further enhance diagnostic accuracy, a multi-protein combined discriminant algorithm was developed incorporating five proteins (hemoglobin beta, cathelicidin-related antimicrobial peptide, talin-1, zyxin, and translationally-controlled tumor protein). The algorithm achieved an AUC of 0.811 and a P-value of < 0.0001, resulting in 79% sensitivity and 71% specificity for the diagnosis of sporadic amyotrophic lateral sclerosis. Subsequently, the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls, as well as patients with different disease severities, was examined. A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls (AUC = 0.766, P < 0.0001). Moreover, the expression of three proteins (FK506 binding protein 1A, cathelicidin-related antimicrobial peptide, and hemoglobin beta-1) was found to increase with disease progression. The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in combination with current clinical-based parameters.
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Ataxia Cerebelar , Encefalite , Transtornos Parkinsonianos , Humanos , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/etiologia , Ataxia/diagnóstico por imagem , Ataxia/etiologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/etiologia , Encefalite/complicações , Encefalite/diagnóstico por imagemRESUMO
Inflammation is considered to be involved in epileptogenesis. However, the relationship between fever and inflammation as well as the mechanisms of fever in the occurrence and development of childhood epilepsy need further investigation. Here, we described an in vivo model of hyperthermia-induced seizures in zebrafish larvae with pentylenetetrazole (PTZ) exposure. Hyperthermia increased the susceptibility to seizure and the production of pro-inflammatory factors in PTZ-induced zebrafish larvae. As mutations in GABRG2 have been associated with fever-associated epilepsy, we used a Tg(hGABRG2F343L) zebrafish model expressing mutant human GABRG2(F343L) to further investigate the involvement of inflammation in fever-induced seizures. Our data indicated that hyperthermia also increased the locomotor activity in Tg(hGABRG2F343L) zebrafish larvae. Although the production of pro-inflammatory factors was upregulated by GABRG2 mutation, hyperthermia did not change the production of pro-inflammatory factors significantly. Lipopolysaccharide (LPS) stimulation was sufficient to increase the locomotor activity in zebrafish larvae, suggesting that inflammation contributed to fever-associated epilepsy. The expression of GABRG2 was increased with PTZ induction, especially at a higher temperature. Moreover, inhibition of inflammation by dexamethasone (DEX) reduced the excitability of zebrafish larvae, especially at a higher temperature. Finally, in vitro experiments proved that LPS stimulation increased the production of IL-1ß and IL-6 in GABRG2(F343L) transfected cells. Collectively, our study demonstrated that neuroinflammation was induced in febrile seizures, and the increased expression of IL-1ß and IL-6 might be responsible for epileptogenesis. The vicious cycle between fever and inflammation might induce seizure onset, and anti-inflammatory strategies might be a potential treatment for fever-associated epilepsy.
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Epilepsia , Convulsões Febris , Animais , Humanos , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/induzido quimicamente , Febre , Inflamação , Interleucina-6/genética , Larva , Lipopolissacarídeos/efeitos adversos , Pentilenotetrazol , Peixe-Zebra , Interleucina-1betaRESUMO
OBJECTIVE: Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock-in mouse with the human infantile spasms-associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3+/N110D knock-in mouse as a model of infantile spasms syndrome. METHODS: We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3+/N110D knock-in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi-unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations. RESULTS: The infantile spasms-associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3+/N110D knock-in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3+/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit. SIGNIFICANCE: The Gabrb3+/N110D knock-in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3+/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits.
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Espasmos Infantis , Humanos , Camundongos , Animais , Espasmos Infantis/genética , Receptores de GABA-A/genética , Convulsões , Células Piramidais , Eletroencefalografia , Síndrome , EspasmoRESUMO
Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.
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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is rare in China. At present, there are no widespread quantitative imaging markers associated with disease severity in MS. Despite several previous studies reporting cerebral blood flow (CBF) changes in MS, no consensus has been reached. In this study, we enrolled 30 Eastern MS patients to investigate CBF changes in different brain regions using the arterial spin labeling technique and their relationship with disease severity. The average CBF in MS patients were higher than those in health controls in various brain regions except cerebellum. The results indicated that MS patients with strongly increased CBF showed worse disease severity, including higher Expanded Disability Status Scale (EDSS) scores and serum neurofilament light chain (sNfL) values than those with mildly increased CBF in the parietal lobes, temporal lobes, basal ganglia, and damaged white matter (DWM). From another perspective, MS patients with worse disease severity (higher EDSS score and sNfL values, longer disease duration) showed increased CBF in parietal lobes, temporal lobes, basal ganglia, normal-appearing white matter (NAWM), and DWM. Correlation analysis showed that there was a strong association among CBF, EDSS score and sNfL. MS patients with strongly increased CBF in various brain regions had more ratio in relapsing phase than patients with mildly increased CBF. And relapsing patients showed significantly higher CBF in some regions (temporal lobes, left basal ganglia, right NAWM) compared to remitting patients. In addition, MS patients with cognitive impairment had higher CBF than those without cognitive impairment in the right parietal lobe and NAWM. However, there were no significant differences in CBF between MS patients with and without other neurologic dysfunctions (e.g., motor impairment, visual disturbance, sensory dysfunction). These findings expand our understanding of CBF in MS and imply that CBF could be a potential quantitative imaging marker associated with disease severity.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Circulação Cerebrovascular/fisiologia , Índice de Gravidade de DoençaRESUMO
SARS-CoV-2 vaccine has considered being the most effective method to prevent SARS-CoV-2 infection. The safety and effectiveness of the SARS-CoV-2 vaccine has been confirmed. However, in very rare cases, autoimmune neurological diseases may occur. In this article, we report three rare cases of autoimmune encephalitis with definite auto-antibody after SARS-CoV-2 vaccination. They all have good prognosis after treatment. In addition, we first use 18F-DPA-714 PET/MRI to evaluate microglia activation in our patients. We found that 18F-DPA-714 PET/MRI may be a powerful tool for quantitative analysis of neuroinflammation in patients of autoimmune encephalitis. Finally, although rare complications may happen after vaccination, we still consider the benefits of vaccination far outweigh the risks. People without contraindications should be vaccinated without delay to prevent infection in current outbreak situation.
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BACKGROUND: As a typical high-disability neurodegenerative disease, Parkinson's disease (PD) progresses variably, and patients who are clinically insensitive to dopaminergic therapy and whose symptoms fail to improve are commonly observed. As a result, achieving early neuron protection is critical. METHODS/DESIGN: The NET-PD study is a 2-year prospective single-center, double-blind, multi-arm, delayed-start, sham-controlled clinical trial assessing the long-term neuroprotective effect of intermittent theta burst stimulation (iTBS) in PD patients. Patients diagnosed with PD, aged 50-80, Hoehn-Yahr stage ≤4, and who maintain medication stability during the study will be enrolled. Clinical assessment and multi-modal markers are used to clarify the clinical improvement and dynamic neuronal changes in PD patients. With a standard deviation of 2, a test level of 0.05, a dropout rate of 10%, and a degree of certainty of 0.9, 60 PD patients are required for this study. RESULTS: The NET-PD project was funded in March 2022, data collection began in July 2022, and is currently in the recruitment phase with two PD patients already enrolled. Data collection is expected to be completed in June 2024. The results are expected for publication in December 2024. DISCUSSION: Previous research has demonstrated a rudimentary method for assessing and delaying PD progression in clinical medication trials. The NET-PD study adopts a rigorous methodology and specific disease-modifying designs to demonstrate the neuroprotective effect of iTBS on PD and investigate the potential mechanism of iTBS in regulating brain and motor functions. We hope to provide supposition for the subsequent exploration of diverse neuroprotection methods.
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Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. At present, no definite ALS biomarkers are available. In this study, exosomes from the plasma of patients with ALS and healthy controls were extracted, and differentially expressed exosomal proteins were compared. Among them, the expression of exosomal coronin-1a (CORO1A) was 5.3-fold higher than that in the controls. CORO1A increased with disease progression at a certain proportion in the plasma of patients with ALS and in the spinal cord of ALS mice. CORO1A was also overexpressed in NSC-34 motor neuron-like cells, and apoptosis, oxidative stress, and autophagic protein expression were evaluated. CORO1A overexpression resulted in increased apoptosis and oxidative stress, overactivated autophagy, and hindered the formation of autolysosomes. Moreover, CORO1A activated Ca2+-dependent phosphatase calcineurin, thereby blocking the fusion of autophagosomes and lysosomes. The inhibition of calcineurin activation by cyclosporin A reversed the damaged autolysosomes. In conclusion, the role of CORO1A in ALS pathogenesis was discovered, potentially affecting the disease onset and progression by blocking autophagic flux. Therefore, CORO1A might be a potential biomarker and therapeutic target for ALS.
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Esclerose Lateral Amiotrófica , Camundongos , Animais , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Calcineurina/metabolismo , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Proteínas dos Microfilamentos/metabolismo , Proteínas do Citoesqueleto/metabolismoRESUMO
BACKGROUND: Anti-IgLON5 disease is a rare neurological disorder associated with autoantibodies against the neuronal cell adhesion protein, IgLON5. Cellular investigations with human IgLON5 antibodies have suggested an antibody-mediated pathogenesis, but whether human IgLON5 autoantibodies can induce disease symptoms in mice is yet to be shown. Moreover, the effects of anti-IgLON5 autoantibodies on neurons and the precise molecular mechanisms in vivo remain controversial. METHODS: We investigated the effects of anti-IgLON5 antibodies in vivo and evaluated their long-term effects. We used two independent passive-transfer animal models and evaluated the effects of the antibodies on mouse behaviors at different time points from day 1 until day 30 after IgG infusion. A wide range of behaviors, including tests of locomotion, coordination, memory, anxiety, depression and social interactions were established. At termination, brain tissue was analyzed for human IgG, neuronal markers, glial markers, synaptic markers and RNA sequencing. RESULTS: These experiments showed that patient's anti-IgLON5 antibodies induced progressive and irreversible behavioral deficits in vivo. Notably, cognitive abnormality was supported by impaired average gamma power in the CA1 during novel object recognition testing. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies in the hippocampus of anti-IgLON5 IgG-injected mice, which persisted 30 days after the injection of patient's antibodies was stopped. Microglial and astrocyte density was increased in the hippocampus of anti-IgLON5 IgG-injected mice at Day 30. Whole-cell voltage clamp recordings proved that anti-IgLON5 antibodies affected synaptic homeostasis. Further western blot investigation of synaptic proteins revealed a reduction of presynaptic (synaptophysin) and post-synaptic (PSD95 and NMDAR1) expression in anti-IgLON5 IgG-injected mice. CONCLUSIONS: Overall, our findings indicated an irreversible effect of anti-IgLON5 antibodies and supported the pathogenicity of these antibodies in vivo.
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Moléculas de Adesão Celular Neuronais , Doenças do Sistema Nervoso , Animais , Autoanticorpos , Moléculas de Adesão Celular Neuronais/metabolismo , Imunoglobulina G/farmacologia , Camundongos , Doenças do Sistema Nervoso/patologia , NeurôniosRESUMO
Immune checkpoint inhibitors (ICIs) are being used in patients with various advanced malignancies, and patient outcomes have improved considerably. Although ICIs can effectively treat tumors, 30-60% of patients experience immune-related adverse events (irAEs). Autoimmune encephalitis (AE) is a rare irAE that has become a novel topic in neuroimmunology and has received increasing attention in recent years. Herein, we report a rare case of GAD65-antibody-associated AE after metastatic small cell lung cancer treatment with pembrolizumab. The patient received IVIg therapy for AE and continuous pembrolizumab therapy without suspension of tumor treatment. At 1 year follow-up, both the patient's AE symptoms and tumors were stable. We consider that the treatment of ICI-associated AE should be more individualized with prudent decision-making and should balance the tumor progression and AE treatment. In addition, we have also comprehensively reviewed the literature of ICI-associated AE, and summarized the clinical features, treatment, and prognosis of AE caused by ICI, thus broadening our understanding of the neurological complications caused by ICI.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, leading to muscle atrophy, paralysis and even death. Immune disorder, redox imbalance, autophagy disorder, and iron homeostasis disorder have been shown to play critical roles in the pathogenesis of ALS. However, the exact pathogenic genes and the underlying mechanism of ALS remain unclear. The purpose of this study was to screen for pathogenic regulatory genes and prognostic markers in ALS using bioinformatics methods. We used Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and expression regulation network analysis to investigate the function of differentially expressed genes in the nerve tissue, lymphoid tissue, and whole blood of patients with ALS. Our results showed that the up-regulated genes were mainly involved in immune regulation and inflammation, and the down-regulated genes were mainly involved in energy metabolism and redox processes. Eleven up-regulated transcription factors (CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, and FOXJ1) and one down-regulated transcription factor (NOG) in the nerve tissue of patients with ALS likely play important regulatory roles in the pathogenesis of ALS. Based on construction and evaluation of the ALS biomarker screening model, cluster analysis of the identified characteristic genes, univariate Cox proportional hazards regression analysis, and the random survival forest algorithm, we found that MAEA, TPST1, IFNGR2, and ALAS2 may be prognostic markers regarding the survival of ALS patients. High expression of MAEA, TPST1, and IFNGR2 and low expression of ALAS2 in ALS patients may be closely related to short survival of ALS patients. Taken together, our results indicate that immune disorders, inflammation, energy metabolism, and redox imbalance may be the important pathogenic factors of ALS. CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, FOXJ1, and NOG may be important regulatory factors linked to the pathogenesis of ALS. MAEA, TPST1, IFNGR2, and ALAS2 are potential important ALS prognostic markers. Our findings provide evidence on the pathogenesis of ALS, potential targets for the development of new drugs for ALS, and important markers for predicting ALS prognosis.
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Mutations in the γ-aminobutyric acid type A (GABAA) receptor γ2 subunit gene, GABRG2, have been associated with a variety of epilepsy syndromes. A de novo mutation (c.T1027C, p.F343L) in GABRG2 was identified in a patient with early onset epileptic encephalopathy. Zebrafish overexpressing mutant human GABRG2 (F343L) subunits displayed spontaneous seizure activity and convulsive behaviors. In this study, we demonstrated that Tg (hGABRG2F343L) zebrafish displayed hyperactivity during light phase with normal circadian rhythm, as well as increased drug-induced locomotor activity. Real-time quantitative PCR, whole mount in situ hybridization and western blotting showed that Tg(hGABRG2F343L) zebrafish had altered expression of GABAA receptor subunits. Furthermore, investigation of synaptic protein expression and synapse ultrastructure uncovered a robust synaptic phenotype that is causally linked to GABRG2(F343L) mutation. Strikingly, Tg(hGABRG2F343L) zebrafish not only had postsynaptic defects, but also displayed an unanticipated deficit at the presynaptic level. Overall, our Tg(hGABRG2F343L) overexpression zebrafish model has expanded the GABAergic paradigm in epileptic encephalopathy from channelopathy to synaptopathy.
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Encefalopatias , Receptores de GABA-A , Animais , Humanos , Mutação , Mutação de Sentido Incorreto/genética , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Convulsões , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Ácido gama-Aminobutírico/genéticaRESUMO
Objective: We aimed to compare the motor effect of bilateral globus pallidus interna (GPi) deep brain stimulation (DBS) on motor subtypes of Parkinson's disease (PD) patients and identify preoperative predictive factors of short-term motor outcome. Methods: We retrospectively investigated bilateral GPi DBS clinical outcomes in 55 PD patients in 1 year follow up. Motor outcome was measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III before and 1 year after surgery. Clinical outcomes were compared among different motor subtypes. Preoperative predictors of motor outcome were assessed by performing univariate and multivariate linear regression and logistic regression analyses. Results: At 1 year following implantation, GPi DBS significantly improved the off-medication MDS-UPDRS III scores in all motor subtype cohorts, with prominent improvement in tremor. No significant difference of postoperative motor symptoms changes was found except greater tremor improvement achieved in both the tremor-dominant (TD) and indeterminate (IND) patients compared to the postural instability and gait difficulty (PIGD) patients. High percentage of PIGD patients were weak responders to DBS. Better levodopa responsiveness and more severe tremor predicted greater overall improvement of motor function in the entire cohort. Similarly, both levodopa responsiveness and tremor improvement were confirmed as predictors for motor improvement in PIGD patients. Conclusion: Bilateral GPi DBS could effectively improve motor outcomes in PD patients regardless of motor subtypes. Both TD and IND patients obtained larger tremor improvement. The intensity of levodopa responsiveness and the severity of tremor could serve as predictors of motor improvement 1 year after GPi DBS.