Neuronal Cell Surface Research Articles

Autoimmune encephalitis with coexisting antibodies to GABABR, GAD65, SOX1 and Ma2

BackgroundAutoimmune encephalitis (AE) is a disease caused by an abnormal reaction between the body’s autoimmunity and the central nervous system, in which the abnormal immune response targets antigenic components within or on the surface of neuronal cells. The main manifestations are mental and behavioural changes, cognitive impairment, impaired consciousness, seizures, movement disorders, etc. Most cell surface antibodies respond well to immunotherapy, intracellular antibodies, on the other hand, are usually associated with more tumours and are relatively difficult to treat with a poor prognosis. In recent years, autoimmune encephalitis that is positive for multiple anti-neuronal antibodies has been gradually recognized in the clinic, with complex and varied clinical manifestations, especially in combination with malignant tumours, which have worse treatment and prognosis. Current clinical studies on the coexistence of multiple anti-neuronal antibodies in patients with AE are mainly disseminated case reports. Patients with AE in which four anti-neuronal antibodies coexist are even rarer.Case presentationWe report a patient who initially presented with an irritating dry cough and hyponatraemia and a chest CT suspicious for malignancy, followed by progressive deterioration of persistent status epilepticus, consciousness and cognitive deficits, and psycho-behavioural abnormalities. Serum and cerebrospinal fluid antibodies against neuronal surface or intracellular antigens were detected using a cell-based assay (CBA) method. Serum and cerebrospinal fluid were found to be positive for anti-GABABR, GAD65, SOX1 and Ma2 antibodies. And a definitive diagnosis of small cell lung cancer was made by immunohistochemistry. He eventually received gammaglobulin, steroid pulsed therapy and tumour chemotherapy.ConclusionsThe coexistence or overlap of multiple anti-neuronal surface antibodies with anti-neuronal intracellular antibodies is rare and increases the likelihood of underlying malignancy. Elucidating the impact of individualized immunotherapy and coexisting antibodies on the clinical presentation of patients has the potential to improve long-term prognosis.

GM1 Oligosaccharide Ameliorates Rett Syndrome Phenotypes In Vitro and In Vivo via Trk Receptor Activation.

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Despite advancements in research, no cure exists due to an incomplete understanding of the molecular effects of MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers of the pathology. Moreover, altered glycosphingolipid metabolism has been reported in RTT. GM1 ganglioside is a known regulator of the nervous system, and growing evidence indicates its importance in maintaining neuronal homeostasis via its oligosaccharide chain, coded as GM1-OS. GM1-OS directly interacts with the Trk receptors on the cell surface, triggering neurotrophic and neuroprotective pathways in neurons. In this study, we demonstrate that GM1-OS ameliorates RTT deficits in the Mecp2-null model. GM1-OS restored synaptogenesis and reduced mitochondrial oxidative stress of Mecp2-knock-out (ko) cortical neurons. When administered in vivo, GM1-OS mitigated RTT-like symptoms. Our findings indicate that GM1-OS effects were mediated by Trk receptor activation on the neuron's plasma membrane. Overall, our results highlight GM1-OS as a promising candidate for RTT treatment.

Functionalized Nanodiamonds for Targeted Neuronal Electromagnetic Signal Detection.

Intracellular sensing technologies necessitate a delicate balance of spatial resolution, sensitivity, biocompatibility, and stability. While existing methods partially fulfill these criteria, none offer a comprehensive solution. Nanodiamonds (NDs) harboring nitrogen-vacancy (NV) centers have emerged as promising candidates due to their sensing capabilities under biological conditions and their ability to meet all aforementioned requirements. This study focuses on expanding the application of NDs and NV center-based sensing to neuronal contexts by investigating their functionalization and subsequent effects on three distinct cell lines relevant to neurodegenerative disease research. Our study concentrates on positioning fluorescent NDs (FNDs) with NV center point defects onto neuronal cell surfaces. Achieving this through specific antibody attachment enhances the proximity of FND to neurites, facilitating the detection of local action potentials. Targeting voltage-dependent calcium channels (Cav2.2) with biotin-streptavidin-bound antibodies enables the precise positioning of FNDs. The functionalized FNDs (f-FNDs) show increased size and zeta potential, confirming the antibody presence without compromising cell viability. Two-color confocal imaging and co-localization algorithms are employed to further attest to the success of the functionalization. The f-FNDs are applied to cell cultures of three cell lines: SH-SY5Y, differentiated dopaminergic neurons, and hippocampal rat neurons; their biocompatibility and effects on synaptic activity are explored. Moreover, preliminary total internal reflection fluorescence - optically detected magnetic resonance (TIRF-ODMR) experiments across cellular sites demonstrate the magnetic field sensitivity of our sensor network. The successful establishment of this sensor network provides a platform for characterizing neuronal signaling in healthy models and conditions mimicking Parkinson's disease.

The Six-Transmembrane Enzyme GDE2 Is Required for the Release of Molecularly Distinct Small Extracellular Vesicles from Neurons.

Extracellular vesicles (EVs) are implicated in a multitude of physiological and pathophysiological processes in the nervous system; however, their biogenesis and cargoes are not well defined. Glycerophosphodiester Phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane protein that cleaves the Glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane and has important roles in neurodevelopment and disease-relevant pathways of neuronal survival. We show here that GDE2 regulates the number of small EVs (sEVs) released from the cell surface of neurons via its GPI-anchor cleavage activity and contributes to the loading of protein cargo through enzymatic and non-enzymatic mechanisms. Proteomic profiling reveals that GDE2 releases at least two distinct EV populations, one containing GDE2 itself and the other harboring the putative ectosomal markers CD9 and BSG. sEVs released by GDE2 are enriched in cytoskeletal and actin-remodeling proteins, suggesting a potential mechanism for GDE2-dependent EV release. Further, sEV populations released by GDE2 are enriched in proteins responsible for modulating synaptic activity and proteins that are critical for cellular redox homeostasis. These studies identify GDE2 as a novel regulator of molecularly distinct sEV populations from neurons with potential roles in the synaptic and redox pathways required for neuronal function and survival.

Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant.

GABABRs are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits. Recently, three variants (G693W, S695I, I705N) have been identified in the gene (GABBR2) encoding for GABABR2. Individuals that harbour any of these variants exhibit severe developmental epileptic encephalopathy and intellectual disability, but the underlying pathogenesis that is triggered in neurons, remains unresolved. Using a range of confocal imaging, flow cytometry, structural modelling, biochemistry, live cell Ca2+ imaging of presynaptic terminals, whole-cell electrophysiology of HEK-293T cells and neurons, and two-electrode voltage clamping of Xenopus oocytes we have probed the biophysical and molecular trafficking and functional profiles of G693W, S695I and I705N variants. We report that all three point mutations impair neuronal cell surface expression of GABABRs, reducing signalling efficacy. However, a negative effect evident for one variant perturbed neurotransmission by elevating presynaptic Ca2+ signalling. This is reversed by enhancing GABABR signalling via positive allosteric modulation. Our results highlight the importance of studying neuronal receptors expressed in nervous system tissue and provide new mechanistic insights into how GABABR variants can initiate neurodevelopmental disease whilst highlighting the translational suitability and therapeutic potential of allosteric modulation for correcting these deficits.

Localized surface plasmon resonance and atomic force microscopy study of model lipid membranes and their interactions with amyloid and melatonin

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. The toxicity of amyloid to neuronal cell surfaces arises from interactions between small intermediate aggregates, namely amyloid oligomers, and the cell membrane. The nature of these interactions changes with age and disease progression. In our previous work, we demonstrated that both membrane composition and nanoscale structure play crucial roles in amyloid toxicity, and that membrane models mimicking healthy neuron were less affected by amyloid than model membranes mimicking AD neuronal membranes. This understanding introduces the possibility of modifying membrane properties with membrane-active molecules, such as melatonin, to protect them from amyloid-induced damage. In this study, we employed atomic force microscopy and localized surface plasmon resonance to investigate the protective effects of melatonin. We utilized synthetic lipid membranes that mimic the neuronal cellular membrane at various stages of AD and explored their interactions with amyloid-β (1–42) in the presence of melatonin. Our findings reveal that the early diseased membrane model is particularly vulnerable to amyloid binding and subsequent damage. However, melatonin exerts its most potent protective effect on this early-stage membrane. These results suggest that melatonin could act at the membrane level to alleviate amyloid toxicity, offering the most protection during the initial stages of AD.

SIGNIFICANCE OF THE NAV 1.8. VOLTAGE-GATED, TETRODOTOXIN-RESISTANT SODIUM CHANNEL FOR THE RENAL SENSORY INNERVATION IN MICE AND RATS

Objective: Our previous work repeatedly showed that the sensory innervation of the kidney in rats has a peculiarity containing predominantly (more than 50%) highly active tonic neurons to electrical stimulation. In a previous publication demonstrated an increased mRNA expression of the TTX-resistant sodium channel Nav1.8 in renal sensory neurons. Hence, we tested the hypothesis that tonic firing pattern is related to the specific expression of Nav1.8 on the cell surface of neurons with renal sensoric axons in the dorsal root ganglia (DRG Th12-L2). Design and method: Harvested dorsal root ganglion neurons (DRG Th11-L2) from Sprague Dawley (SD) with renal afferents were investigated in neuronal cell culture using current clamp mode to assess action potential generation during current injection and to characterize neurons as tonic highly active and phasic less active neurons using a Nav1.8 blocker (A-803467) before and after stimulation. Further, renal DRG neurons from a Nav1.8 knock out mouse (C57BL6J-Scn10atm1Jwo) were investigated in a current clamp mode. C57BL6 mice were used as controls. Results: At a concentration of 0.3μM the maximum AP firing frequency of tonic neurons was blocked from 13+/- 1.1 APs/600ms to 7.6+/-1.4 APs/600ms under superfusion with a Nav1.8 blocker. No blocker effects were seen at a concentration of 0.1 μM and due to superfusion with the solvent methanol alone. The firing pattern of renal neurons in the C57BL6 mouse was similar to that in the SD rat with a dominance of the tonic highly active neurons. In a Nav1.8 knock out mouse (C57BL6J-Scn10atm1Jwo) in the population of neurons with dendrites from the kidney only a single cell out of 70 showed tonic firing behavior (control vs Nav1.8 KO mouse, z-test, p<0.05). Conclusions: Under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings in this study support the significance of the TTX-resistant sodium channel Nav1.8 for the specific tonic firing pattern of neurons with renal projections. That might be of importance for pharmacological interventions to influence renal nerve activity, which likely plays a crucial role in the regulation of blood pressure and control of cardiovascular function.

B-cell targeted therapies in autoimmune encephalitis: mechanisms, clinical applications, and therapeutic potential.

Autoimmune encephalitis (AE) broadly refers to inflammation of the brain parenchyma mediated by autoimmune mechanisms. In most patients with AE, autoantibodies against neuronal cell surface antigens are produced by B-cells and induce neuronal dysfunction through various mechanisms, ultimately leading to disease progression. In recent years, B-cell targeted therapies, including monoclonal antibody (mAb) therapy and chimeric antigen receptor T-cell (CAR-T) therapy, have been widely used in autoimmune diseases. These therapies decrease autoantibody levels in patients and have shown favorable results. This review summarizes the mechanisms underlying these two B-cell targeted therapies and discusses their clinical applications and therapeutic potential in AE. Our research provides clinicians with more treatment options for AE patients whose conventional treatments are not effective.

The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses

Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki Forest virus. Domain mapping and binding studies reveal a low-affinity interaction with LA domain 3 (LA3) that can be enhanced by concatenation of LA3 repeats. Soluble decoy proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice. Our results establish LDLR as a low-affinity receptor for multiple alphaviruses and highlight a possible path for developing inhibitors that could mitigate infection and disease.

Assessment of the relationship between the dopaminergic pathway and severe acute respiratory syndrome coronavirus 2 infection, with related neuropathological features, and potential therapeutic approaches in COVID-19 infection.

Dopamine is a known catecholamine neurotransmitter involved in several physiological processes, including motor control, motivation, reward, cognition, and immune function. Dopamine receptors are widely distributed throughout the nervous system and in immune cells. Several viruses, including human immunodeficiency virus and Japanese encephalitis virus, can use dopaminergic receptors to replicate in the nervous system and are involved in viral neuropathogenesis. In addition, studies suggest that dopaminergic receptors may play a role in the progression and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. When SARS-CoV-2 binds to angiotensin-converting enzyme 2 receptors on the surface of neuronal cells, the spike protein of the virus can bind to dopaminergic receptors on neighbouring cells to accelerate its life cycle and exacerbate neurological symptoms. In addition, recent research has shown that dopamine is an important regulator of the immune-neuroendocrine system. Most immune cells express dopamine receptors and other dopamine-related proteins, indicating the importance of dopaminergic immune regulation. The increase in dopamine concentration during SARS-CoV2 infection may reduce immunity (innate and adaptive) that promotes viral spread, which could lead to neuronal damage. In addition, dopaminergic signalling in the nervous system may be affected by SARS-CoV-2 infection. COVID -19 can cause various neurological symptoms as it interacts with the immune system. One possible treatment strategy for COVID -19 patients could be the use of dopamine antagonists. To fully understand how to protect the neurological system and immune cells from the virus, we need to study the pathophysiology of the dopamine system in SARS-CoV-2 infection.

Scanning Ion-Conductance Microscopy for Studying β-Amyloid Aggregate Formation on Living Cell Surfaces.

β-Amyloid aggregation on living cell surfaces is described as responsible for the neurotoxicity associated with different neurodegenerative diseases. It is suggested that the aggregation of β-amyloid (Aβ) peptide on neuronal cell surface leads to various deviations of its vital function due to myriad pathways defined by internalization of calcium ions, apoptosis promotion, reduction of membrane potential, synaptic activity loss, etc. These are associated with structural reorganizations and pathologies of the cell cytoskeleton mainly involving actin filaments and microtubules and consequently alterations of cell mechanical properties. The effect of amyloid oligomers on cells' Young's modulus has been observed in a variety of studies. However, the precise connection between the formation of amyloid aggregates on cell membranes and their effects on the local mechanical properties of living cells is still unresolved. In this work, we have used correlative scanning ion-conductance microscopy (SICM) to study cell topography, Young's modulus mapping, and confocal imaging of Aβ aggregate formation on living cell surfaces. However, it is well-known that the cytoskeleton state is highly connected to the intracellular level of reactive oxygen species (ROS). The effect of Aβ leads to the induction of oxidative stress, actin polymerization, and stress fiber formation. We measured the reactive oxygen species levels inside single cells using platinum nanoelectrodes to demonstrate the connection of ROS and Young's modulus of cells. SICM can be successfully applied to studying the cytotoxicity mechanisms of Aβ aggregates on living cell surfaces.

Increased neuropil antibody prevalence in COVID-19 patients with acute ischemic stroke

ABSTRACT Objectives COVID-19 infection is associated with an increased risk of acute ischemic stroke (AIS). Although the underlying mechanisms are largely unknown, autoimmunity has been implicated as a potential role player. Methods To investigate the presence and clinical impact of neuronal cell surface antibodies in COVID-19 associated AIS, patients with COVID-19 pneumonia and AIS (n = 30), COVID-19 pneumonia without AIS (n = 32) and AIS without COVID-19 infection (n = 27) were recruited. Serum anti-neuronal antibodies directed against well-characterized and novel cell surface antibodies were evaluated by cell-based assays and indirect immunohistochemistry, respectively. Results None of the recruited patients displayed well-characterized neuronal cell surface antibodies. Ten patients in the COVID-19 pneumonia with AIS group and three patients in the COVID-19 pneumonia without AIS group exhibited antibodies to neuropil of hippocampus and cerebellum. Neuropil-antibody positive patients showed trends towards milder clinical severity and reduced blood levels of inflammation factors. Conclusion Our results confirm the presence of neuropil antibodies in patients with COVID-19 infection and identify a putative antibody-driven association between AIS and COVID-19. The antigenic targets and potential pathogenic action of these antibodies need to be further explored.

Autoimmune encephalitis, a diagnostic and therapeutic challenge in the intensive care unit

Autoimmune encephalitis is a progressive inflammation of the brain, from acute to subacute, associated with antibodies against neuronal cell surface and synaptic protein, most commonly encephalitis against the N-methyl-D-aspartate (NMDA) receptor. New significant findings on etiology show that autoimmune encephalitis is triggered by several etiologies, for example neoplastic processes (breast, lung, kidney, thyroid cancer, ovarian teratoma, and B-cell lymphoma) but also by infections of the nervous system, such as herpes encephalitis. Antibodies against neuronal surface structures are usually direct pathogens and develop their effect through internalization of target proteins, through receptor blockade or complement activation. The type and titer of the antibody e.g. against NMDA receptors, Gamma Amino Butyric (GABA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or voltage-gated potassium channel complexes. An associated tumor, biomarkers, imaging studies, and cerebrospinal fluid are decisive for the prognosis. We present the clinical case of a male patient in the fourth decade of life who is diagnosed with autoimmune encephalitis, we will address the diagnosis and treatment.

The GTPase Rab21 is required for neuronal development and migration in the cerebral cortex.

Development of the mammalian neocortex requires proper inside-out migration of developing cortical neurons from the germinal ventricular zone toward the cortical plate. The mechanics of this migration requires precise coordination of different cellular phenomena including cytoskeleton dynamics, membrane trafficking, and cell adhesion. The small GTPases play a central role in all these events. The small GTPase Rab21 regulates migration and neurite growth in developing neurons. Moreover, regulators and effectors of Rab21 have been implicated in brain pathologies with cortical malformations, suggesting a key function for the Rab21 signaling pathway in cortical development. Mechanistically, it has been posited that Rab21 influences cell migration by controlling the trafficking of endocytic vesicles containing adhesion molecules. However, direct evidence of the participation of Rab21 or its mechanism of action in the regulation of cortical migration is still incomplete. In this study, we demonstrate that Rab21 plays a critical role in the differentiation and migration of pyramidal neurons by regulating the levels of the amyloid precursor protein on the neuronal cell surface. Rab21 loss of function increased the levels of membrane-exposed APP, resulting in impaired cortical neuronal differentiation and migration. These findings further our understanding of the processes governing the development of the cerebral cortex and shed light onto the molecular mechanisms behind cortical development disorders derived from the malfunctioning of Rab21 signaling effectors.

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain.

Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a complex mechanism that tends to worsen over time, leading to a significant deterioration in patients' quality of life and issues like depression, disability, and disturbed sleep. Presently used analgesics are not effective enough in neuropathy treatment and may cause many side effects due to the high doses needed. In recent years, many researchers have pointed to the important role of chemokines not only in the development and maintenance of neuropathy but also in the effectiveness of analgesic drugs. Currently, approximately 50 chemokines are known to act through 20 different seven-transmembrane G-protein-coupled receptors located on the surface of neuronal, glial, and immune cells. Data from recent years clearly indicate that more chemokines than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) have pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting their synthesis, or blocking their receptors brings neuropathic pain relief. Several of them (CCL1/2/3/7/9/XCL1) have been shown to be able to reduce opioid drug effectiveness in neuropathy, and neutralizing antibodies against them can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence that chemokine receptors are promising targets for pharmacotherapy; chemokine receptor antagonists can relieve pain of different etiologies, and most of them are able to enhance opioid analgesia, for example, the blockade of CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), and XCR1 (vMIP-II). Recent research has shown that multitarget antagonists of chemokine receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), and CCR2/CCR5/CCR8 (RAP-103), are also very effective painkillers. A multidirectional strategy based on the modulation of neuronal-glial-immune interactions by changing the activity of the chemokine family can significantly improve the quality of life of patients suffering from neuropathic pain. However, members of the chemokine family are still underestimated pharmacological targets for pain treatment. In this article, we review the literature and provide new insights into the role of chemokines and their receptors in neuropathic pain.

Clinical study of autonomic dysfunction in patients with autoimmune encephalitis

BackgroundAutoimmune encephalitis (AE) is a collective name, covering an emerging spectrum of autoimmune-mediated neurological diseases related to antibodies and synaptic or intracellular proteins. Anti-NMDAR, anti-LGI1, and anti-GABABR are three types of neuronal cell surface antibodies. Autonomic dysfunction represents a frequently occurring clinical manifestation. This observational study purposes to investigate comparisons between two groups with or without autonomic dysfunction and detect the autonomic dysfunction and other indexes in anti-NMDAR, anti-LGI1, and anti-GABABR cohorts. MethodsPatients with anti-NMDAR, anti-LGI1 and anti-GABABR encephalitis were recruited from the May 2017 to the April 2022. The following information was recorded: age, age at onset, tumor presence, gender, prodromal symptoms, clinical manifestations, cranial magnetic resonance imaging, cerebrospinal fluid and blood examinations, and immunotherapy. ResultsThere were totally 161 patients enrolled in this study. Among these participants, 104 individuals (64.6%) presented autonomic dysfunction and the remaining 57 (35.4%) were free of autonomic dysfunction. Sinus tachycardia was the most common autonomic dysfunction, followed by pollakiuria/uroclepsia, feverscence, central hypoventilation, sinus bradycardia, constipation, uroschesis, hyperhidrosis, hypersalivation, hypotension, and early satiety/emesis. Compared to patients without autonomic dysfunction, those with autonomic dysfunction had a higher incidence of central hypoventilation and ICU admissions. Meanwhile, in both groups with or without autonomic dysfunction, meatal behavior disorder, cognitive impairment, and epileptic seizure were three most common clinical manifestations. There were no significant differences in cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) examination, antibody titers and number of immunotherapy types. Further analysis of AE mediated by distinct neuronal surface antibodies demonstrated that there were 85 anti-NMDAR, 56 anti-LGI1, and 20 anti-GABABR encephalitis patients. The significant differences between these three cohorts appeared in age, tumor presence, fervescence presence and antibody titers. ConclusionThis study demonstrated the comparisons between autonomic dysfunction group and autonomic dysfunction-free group and provided insights into better diagnosis and treatment.

Endogenous Glycoprotein GPM6a Is Involved in Neurite Outgrowth in Rat Dorsal Root Ganglion Neurons.

The peripheral nervous system (PNS) has a unique ability for self-repair. Dorsal root ganglion (DRG) neurons regulate the expression of different molecules, such as neurotrophins and their receptors, to promote axon regeneration after injury. However, the molecular players driving axonal regrowth need to be better defined. The membrane glycoprotein GPM6a has been described to contribute to neuronal development and structural plasticity in central-nervous-system neurons. Recent evidence indicates that GPM6a interacts with molecules from the PNS, although its role in DRG neurons remains unknown. Here, we characterized the expression of GPM6a in embryonic and adult DRGs by combining analysis of public RNA-seq datasets with immunochemical approaches utilizing cultures of rat DRG explants and dissociated neuronal cells. M6a was detected on the cell surfaces of DRG neurons throughout development. Moreover, GPM6a was required for DRG neurite elongation in vitro. In summary, we provide evidence on GPM6a being present in DRG neurons for the first time. Data from our functional experiments support the idea that GPM6a could contribute to axon regeneration in the PNS.

S100A6 participates in initiation of autoimmune encephalitis and is under epigenetic control.

Autoimmune encephalitis (AE) is caused by autoantibodies attacking neuronal cell surface antigens and/or synaptic antigens. We previously demonstrated that S100A6 was hypomethylated in patients with AE and that it promoted B lymphocyte infiltration through the simulated blood-brain barrier (BBB). In this study, we focused on the epigenetic regulation of S100A6, the process by which S100A6 affects B lymphocyte infiltration, and the therapeutic potential of S100A6 antibodies. We enrolled and collected serum from 10 patients with AE and 10 healthy control (HC) subjects. Promoter methylation and 5-azacytidine treatment assays were conducted to observe the methylation process of S100A6. The effect of S100A6 on B lymphocytes was analyzed using an adhesion assay and leukocyte transendothelial migration (LTEM) assay. A LTEM assay was also used to compare the effects of the serum of HCs, serum of AE patients, S100A6 recombinant protein, and S100A6 antibodies on B lymphocytes. The promoter methylation and 5-azacytidine treatment assays confirmed that S100A6 was regulated by DNA methylation. The adhesion study demonstrated that the addition of S100A6 enhanced adhesion between B lymphocytes and a BBB endothelial cell line in a concentration-dependent manner. The LTEM assay showed that the serum of AE patients, as well as S100A6, promoted B lymphocyte infiltration and that this effect could be attenuated by S100A6 antibodies. We clarified that S100A6 was under epigenetic regulation in patients with AE and that it helped B lymphocytes to adhere to and infiltrate the BBB endothelial layer, which could be counteracted by S100A6 antibodies. Therefore, the methylation profile of S100A6 could be a marker of the activity of AE, and countering the effect of S100A6 may be a potential treatment target for AE.

Anti-NMDAR antibodies, watch the company they keep

Anti-N-methyl D-aspartate receptor (anti-NMDAR) encephalitis is the most common and best described of the autoimmune encephalitis syndromes associated with neuronal cell surface or synaptic autoantibodies. It is typically characterised by a progressive clinical course involving confusion, psychosis, seizures, dysautonomia and altered consciousness and has increasingly been a diagnostic consideration for clinicians given greater awareness of its serious nature and potential response to immunosuppressive therapy.

Autoimmune Encephalitis, a Diagnostic and Therapeutic Challenge in the Intensive Care Unit.

Autoimmune encephalitis is a progressive inflammation of the brain, from acute to subacute, associated with antibodies against neuronal cell surface and synaptic protein, most commonly encephalitis against the N-methyl-D-aspartate (NMDA) receptor. New significant findings on etiology show that autoimmune encephalitis is triggered by several etiologies, for example neoplastic processes (breast, lung, kidney, thyroid cancer, ovarian teratoma, and B-cell lymphoma) but also by infections of the nervous system, such as herpes encephalitis. Antibodies against neuronal surface structures are usually direct pathogens and develop their effect through internalization of target proteins, through receptor blockade or complement activation. The type and titer of the antibody e.g. against NMDA receptors, Gamma Amino Butyric (GABA), αAmino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or voltage-gated potassium channel complexes. An associated tumor, biomarkers, imaging studies, and cerebrospinal fluid are decisive for the prognosis. We present the clinical case of a male patient in the fourth decade of life who is diagnosed with autoimmune encephalitis, we will address the diagnosis and treatment