The Experts below are selected from a list of 4626 Experts worldwide ranked by ideXlab platform
Masaki Fukata - One of the best experts on this subject based on the ideXlab platform.
-
Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability
Annals of neurology, 2020Co-Authors: Hanschristian Kornau, Yuko Fukata, Jakob Kreye, Alexander Stumpf, Daniel Parthier, Rosanna P Sammons, Barbara Imbrosci, Sarah Kurpjuweit, Alexander B. Kowski, Masaki FukataAbstract:Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418. © 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
-
Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination
Development, 2014Co-Authors: Linde Kegel, Siska Driegen, Eerik Aunin, Kris Leslie, Yuko Fukata, Masaki Fukata, Masahiko Watanabe, Martine Jaegle, Dies MeijerAbstract:The cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution.
-
autoantibodies to epilepsy related LGI1 in limbic encephalitis neutralize LGI1 adam22 interaction and reduce synaptic ampa receptors
The Journal of Neuroscience, 2013Co-Authors: Toshika Ohkawa, Yuko Fukata, Miwako Yamasaki, Taisuke Miyazaki, Osamu Watanabe, Hiroshi Takashima, Norihiko Yokoi, Masahiko Watanabe, Masaki FukataAbstract:More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life.
-
leucine rich glioma inactivated 1 LGI1 an epilepsy related secreted protein has a nuclear localization signal and localizes to both the cytoplasm and the nucleus of the caudal ganglionic eminence neurons
European Journal of Neuroscience, 2012Co-Authors: Sayaka Kusuzawa, Yuko Fukata, Masaki Fukata, Takao Honda, Shigeaki Kanatani, Daisuke H Tanaka, Kazunori NakajimaAbstract:Leucine-rich glioma inactivated 1 (LGI1) is a secreted synaptic protein that organizes a transsynaptic protein complex throughout the brain. Mutations in the LGI1 gene have been found in patients with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although a large number of studies have focused on the expression and function of LGI1 in the postnatal brain, information regarding its functions and distribution during development remains sparse. Here we report that LGI1 mRNA is preferentially expressed in the caudal ganglionic eminence (CGE) of the early embryonic telencephalon, and LGI1 protein is unexpectedly localized in the nucleus of dissociated CGE neurons. Using bioinformatics analysis, we found that LGI1 contains a putative nuclear localization signal (NLS) in its leucine-rich repeat C-terminal domain. Furthermore, we show that the transient expression of LGI1 in CGE neurons resulted in nuclear translocation of the LGI1 protein, and a mutation in the NLS led to the retention of LGI1 in the cytoplasm. We also confirmed that the NLS sequence of LGI1 had the ability to mediate the nuclear localization by using the NLS-containing fusion protein. Interestingly, when LGI1 was expressed in neurons obtained from the medial ganglionic eminence or cerebral cortex, almost no nuclear localization of LGI1 was observed. These results raise the possibility of a novel role of LGI1 within embryonic neurons through nuclear translocation and may provide insight into its potential effects on the development of the central nervous system and ADLTE pathogenesis.
-
disruption of LGI1 linked synaptic complex causes abnormal synaptic transmission and epilepsy
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Yuko Fukata, Kathryn Lynn Lovero, Tsuyoshi Iwanaga, Roger A. Nicoll, Ryuichi Shigemoto, Norihiko Yokoi, Katsuhiko Tabuchi, Atsushi Watanabe, Masaki FukataAbstract:Epilepsy is a devastating and poorly understood disease. Mutations in a secreted neuronal protein, leucine-rich glioma inactivated 1 (LGI1), were reported in patients with an inherited form of human epilepsy, autosomal dominant partial epilepsy with auditory features (ADPEAF). Here, we report an essential role of LGI1 as an antiepileptogenic ligand. We find that loss of LGI1 in mice (LGI1−/−) causes lethal epilepsy, which is specifically rescued by the neuronal expression of LGI1 transgene, but not LGI3. Moreover, heterozygous mice for the LGI1 mutation (LGI1+/−) show lowered seizure thresholds. Extracellularly secreted LGI1 links two epilepsy-related receptors, ADAM22 and ADAM23, in the brain and organizes a transsynaptic protein complex that includes presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. A lack of LGI1 disrupts this synaptic protein connection and selectively reduces AMPA receptor–mediated synaptic transmission in the hippocampus. Thus, LGI1 may serve as a major determinant of brain excitation, and the LGI1 gene-targeted mouse provides a good model for human epilepsy.
John K Cowell - One of the best experts on this subject based on the ideXlab platform.
-
Inactivation of LGI1 in murine neuronal precursor cells leads to dysregulation of axon guidance pathways
Genomics, 2019Co-Authors: Jeane Silva, Lesleyann Hawthorn, John K CowellAbstract:Abstract LGI1 mutations predispose to a rare epilepsy syndrome and when inactivated in mice leads to early onset seizures and premature death. Histopathology of the mature brain soon after birth shows cortical dysplasia in LGI1 null mice with hypercellularity in the outer cortical layers. Here we show extensive gene expression changes in neuronal precursor cells from LGI1 null mice compared with wild type mice. The most significantly dysregulated pathway involves canonical axon guidance signaling with multiple networks involved in cell movement, adhesion and invasion related to actin cytoskeleton reorganization. The LGI1 null NPCs show increased cell motility in vitro compared with normal counterparts. Dysregulation of genes critical to cell movement/migration and critical transcription factors involved in early neuronal development is a prominent feature. These studies provide a critical mechanistic link to the observation of increased cellularity in the outer layers of the developing cortex in LGI1 null mice.
-
Selective inactivation of LGI1 in neuronal precursor cells leads to cortical dysplasia in mice.
Genesis (New York N.Y. : 2000), 2018Co-Authors: Jeane Silva, Haiyan Qin, John K CowellAbstract:Constitutional mutations in Leucine-rich glioma inactivated 1 (LGI1) predispose to an autosomal dominant epilepsy syndrome in humans and germline inactivation of LGI1 in mice leads to early onset seizures. LGI1 is highly expressed in the regions involved in neuronal stem cell generation and migration and detailed analysis of the brains in these mice reveals a subtle cortical dysplasia characterized by hypercellularity in the outer cortical layers. To investigate the cellular origin for this cortical dysplasia, we created mice that allow cell-specific, conditional inactivation of LGI1. Exons 3-4, which contain critical motifs for LGI1 function, were targeted for deletion and, using a CMV-cre mouse strain, global inactivation of LGI1 led to early onset seizures and the same cortical dysplasia seen in the constitutionally null mice. Similarly, inactivation of LGI1 in cells expressing Nestin, expressed primarily in neuronal precursor cells, led to early onset seizures and cortical dysplasia. In contrast, targeting inactivation of LGI1 in cells expressing Gfap, Camk2a, and parvalbumin, did not lead to cortical dysplasia. This strain of mouse, therefore, allows for a more refined investigation of the cell types involved in the cortical dysplasia seen following inactivation of LGI1 and potentially a better understanding of the molecular mechanisms behind LGI1-induced epilepsy.
-
LGI1: from zebrafish to human epilepsy.
Progress in Brain Research, 2014Co-Authors: John K CowellAbstract:Mutations in the LGI1 gene predispose to autosomal dominant lateral temporal lobe epilepsy, a rare hereditary form with incomplete penetrance and associated with acoustic auras. LGI1 is not a structural component of an ion channel like most epilepsy-related genes, but is a secreted protein. Mutant null mice exhibit early-onset seizures, and electrophysiological analysis shows abnormal synaptic transmission. LGI1 binds to ADAM23 on the presynaptic membrane and ADAM22 on the postsynaptic membrane, further implicating it in regulating the strength of synaptic transmission. Patients with limbic encephalitis show autoantibodies against LGI1 and develop seizures, supporting a role for LGI1 in synapse transmission in the post developmental brain. LGI1, however, also seems to be involved in aspects of neurite development and dendritic pruning, suggesting an additional role in corticogenesis. LGI1 is also involved in cell movement and suppression of dendritic outgrowth in in vitro systems, possibly involving actin cytoskeleton dynamics. Expression patterns in embryonic development correspond to areas of neuronal migration. Loss of LGI1 expression also impacts on myelination of the central and peripheral nervous systems. In zebrafish embryos, knockdown of LGI1a leads to a seizure-like behavior and abnormal brain development, providing a system to study its role in early embryogenesis. Despite being implicated in a role in both synapse transmission and neuronal development, how LGI1 predisposes to epilepsy is still largely unknown. It appears, however, that LGI1 may function differently in a cell context-specific manner, implying a complex involvement in brain development and function that remains to be defined.
-
investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels a case series
Lancet Neurology, 2010Co-Authors: Maartje G Huijbers, Eric Lancaster, Luis Bataller, Rita J Balicegordon, John K Cowell, Francesc Graus, Josep DalmauAbstract:Summary Background Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. Methods We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of LGI1 -null mice. Findings Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and LGI1 -null mice, which showed selective lack of reactivity in brains of LGI1 -null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan's syndrome, and neuromyotonia. Interpretation LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. Funding National Institutes of Health, National Cancer Institute, and Euroimmun.
-
Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series
The Lancet. Neurology, 2010Co-Authors: Meizan Lai, Eric Lancaster, Maartje G Huijbers, Luis Bataller, John K Cowell, Francesc Graus, Rita J. Balice-gordon, Josep DalmauAbstract:Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of LGI1-null mice. Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and LGI1-null mice, which showed selective lack of reactivity in brains of LGI1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan's syndrome, and neuromyotonia. LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. National Institutes of Health, National Cancer Institute, and Euroimmun. Copyright 2010 Elsevier Ltd. All rights reserved.
Yuko Fukata - One of the best experts on this subject based on the ideXlab platform.
-
human cerebrospinal fluid monoclonal LGI1 autoantibodies increase neuronal excitability
Annals of Neurology, 2020Co-Authors: Yuko Fukata, Hanschristian Kornau, Jakob Kreye, Alexander Stumpf, Daniel Parthier, Rosanna P Sammons, Barbara ImbrosciAbstract:Objective Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. Methods We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Results Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.
-
Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability
Annals of neurology, 2020Co-Authors: Hanschristian Kornau, Yuko Fukata, Jakob Kreye, Alexander Stumpf, Daniel Parthier, Rosanna P Sammons, Barbara Imbrosci, Sarah Kurpjuweit, Alexander B. Kowski, Masaki FukataAbstract:Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418. © 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
-
Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy
Nature Medicine, 2015Co-Authors: Norihiko Yokoi, Yuko Fukata, Toshika Ohkawa, Taisuke Miyazaki, Daisuke Kase, Naoki Takahashi, Hiroko Iwanari, Yasuhiro Mochizuki, Martine Jaegle, Takao HamakuboAbstract:Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1 , encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1^E383A protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1^S473L protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1^E383A folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1^E383A model mice. This study establishes LGI1 -related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy. New mouse models help unravel the mechanisms through which LGI1 missense mutations cause epilepsy.
-
Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination
Development, 2014Co-Authors: Linde Kegel, Siska Driegen, Eerik Aunin, Kris Leslie, Yuko Fukata, Masaki Fukata, Masahiko Watanabe, Martine Jaegle, Dies MeijerAbstract:The cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution.
-
autoantibodies to epilepsy related LGI1 in limbic encephalitis neutralize LGI1 adam22 interaction and reduce synaptic ampa receptors
The Journal of Neuroscience, 2013Co-Authors: Toshika Ohkawa, Yuko Fukata, Miwako Yamasaki, Taisuke Miyazaki, Osamu Watanabe, Hiroshi Takashima, Norihiko Yokoi, Masahiko Watanabe, Masaki FukataAbstract:More than 30 mutations in LGI1, a secreted neuronal protein, have been reported with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although LGI1 haploinsufficiency is thought to cause ADLTE, the underlying molecular mechanism that results in abnormal brain excitability remains mysterious. Here, we focused on a mode of action of LGI1 autoantibodies associated with limbic encephalitis (LE), which is one of acquired epileptic disorders characterized by subacute onset of amnesia and seizures. We comprehensively screened human sera from patients with immune-mediated neurological disorders for LGI1 autoantibodies, which also uncovered novel autoantibodies against six cell surface antigens including DCC, DPP10, and ADAM23. Our developed ELISA arrays revealed a specific role for LGI1 antibodies in LE and concomitant involvement of multiple antibodies, including LGI1 antibodies in neuromyotonia, a peripheral nerve disorder. LGI1 antibodies associated with LE specifically inhibited the ligand-receptor interaction between LGI1 and ADAM22/23 by targeting the EPTP repeat domain of LGI1 and reversibly reduced synaptic AMPA receptor clusters in rat hippocampal neurons. Furthermore, we found that disruption of LGI1-ADAM22 interaction by soluble extracellular domain of ADAM22 was sufficient to reduce synaptic AMPA receptors in rat hippocampal neurons and that levels of AMPA receptor were greatly reduced in the hippocampal dentate gyrus in the epileptic LGI1 knock-out mouse. Therefore, either genetic or acquired loss of the LGI1-ADAM22 interaction reduces the AMPA receptor function, causing epileptic disorders. These results suggest that by finely regulating the synaptic AMPA receptors, the LGI1-ADAM22 interaction maintains physiological brain excitability throughout life.
Philip A. Barker - One of the best experts on this subject based on the ideXlab platform.
-
The Nogo Receptor Ligand LGI1 Regulates Synapse Number and Synaptic Activity in Hippocampal and Cortical Neurons.
eNeuro, 2018Co-Authors: Rhalena A. Thomas, Stéphanie Baulac, Julien Gibon, Carol X.-q. Chen, Sabrina Chierzi, Vincent G. Soubannier, Philippe Séguéla, Keith K. Murai, Philip A. BarkerAbstract:Leucine-rich glioma-inactivated protein 1 (LGI1) is a secreted neuronal protein and a Nogo receptor 1 (NgR1) ligand. Mutations in LGI1 in humans causes autosomal dominant lateral temporal lobe epilepsy and homozygous deletion of LGI1 in mice results in severe epileptic seizures that cause early postnatal death. NgR1 plays an important role in the development of CNS synapses and circuitry by limiting plasticity in the adult cortex via the activation of RhoA. These relationships and functions prompted us to examine the effect of LGI1 on synapse formation in vitro and in vivo. We report that application of LGI1 increases synaptic density in neuronal culture and that LGI1 null hippocampus has fewer dendritic mushroom spines than in wild-type (WT) littermates. Further, our electrophysiological investigations demonstrate that LGI1 null hippocampal neurons possess fewer and weaker synapses. RhoA activity is significantly increased in cortical cultures derived from LGI1 null mice and using a reconstituted system; we show directly that LGI1 antagonizes NgR1-tumor necrosis factor receptor orphan Y (TROY) signaling. Our data suggests that LGI1 enhances synapse formation in cortical and hippocampal neurons by reducing NgR1 signaling.
-
Identification of genetic variants of LGI1 and RTN4R (NgR1) linked to schizophrenia that are defective in NgR1-LGI1 signaling.
Molecular genetics & genomic medicine, 2016Co-Authors: Rhalena A. Thomas, Amirthagowri Ambalavanan, Guy A. Rouleau, Philip A. BarkerAbstract:The protein NgR1 is encoded by RTN4R, a gene linked to schizophrenia. We previously reported NgR1 as receptor for the epilepsy-linked protein LGI1. NgR1 regulates synapse number and synaptic plasticity, whereas LGI1 antagonizes NgR1 signaling and promotes synapse formation. Impairments in synapse formation are common in neurological disease and we hypothesized that an LGI1-NgR1 signaling pathway may contribute to the development of schizophrenia. We screened two unrelated schizophrenic populations for variants in RTN4R and LGI1 using whole exome sequencing and Sanger sequencing. We tested the ability of LGI1 to bind rare coding variants of NgR1 using a cell surface binding assays and the signaling ability of NgR1 using COS7 cell-spreading assays. We observed a previously reported rare coding variant in RTN4R (c.1195C>T, pR399W). We report the first LGI1 mutations to be identified in individuals with schizophrenia. Three different LGI1 mutations were found, two missense mutations (c.205G>A, p.V69I) and (c.313G>A, V105M), and an intronic variant (g.897T>C) that likely leads to a protein truncation. We found NgR1(R119W) and NgR1(277C) have a reduced ability to bind LGI1 in a cell surface binding assay. COS7 cell-spreading assays reveal that NgR1 mutants are impaired in their ability to mediate RhoA activation. Variants in NgR1 and LGI1 may be associated with schizophrenia and variants in NgR1 found in schizophrenic patients have impaired LGI1-NgR1 signaling. Impaired LGI1-NgR1 signaling may contribute to disease progression.
-
identification of genetic variants of LGI1 and rtn4r ngr1 linked to schizophrenia that are defective in ngr1 LGI1 signaling
Molecular Genetics & Genomic Medicine, 2016Co-Authors: Rhalena A. Thomas, Philip A. Barker, Amirthagowri Ambalavanan, Guy A. RouleauAbstract:Background The protein NgR1 is encoded by RTN4R, a gene linked to schizophrenia. We previously reported NgR1 as receptor for the epilepsy-linked protein LGI1. NgR1 regulates synapse number and synaptic plasticity, whereas LGI1 antagonizes NgR1 signaling and promotes synapse formation. Impairments in synapse formation are common in neurological disease and we hypothesized that an LGI1–NgR1 signaling pathway may contribute to the development of schizophrenia. Methods We screened two unrelated schizophrenic populations for variants in RTN4R and LGI1 using whole exome sequencing and Sanger sequencing. We tested the ability of LGI1 to bind rare coding variants of NgR1 using a cell surface binding assays and the signaling ability of NgR1 using COS7 cell-spreading assays. Results We observed a previously reported rare coding variant in RTN4R (c.1195C>T, pR399W). We report the first LGI1 mutations to be identified in individuals with schizophrenia. Three different LGI1 mutations were found, two missense mutations (c.205G>A, p.V69I) and (c.313G>A, V105M), and an intronic variant (g.897T>C) that likely leads to a protein truncation. We found NgR1R119W and NgR1277C have a reduced ability to bind LGI1 in a cell surface binding assay. COS7 cell-spreading assays reveal that NgR1 mutants are impaired in their ability to mediate RhoA activation. Conclusion Variants in NgR1 and LGI1 may be associated with schizophrenia and variants in NgR1 found in schizophrenic patients have impaired LGI1–NgR1 signaling. Impaired LGI1–NgR1 signaling may contribute to disease progression.
-
The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface
Human molecular genetics, 2006Co-Authors: Maria Salomé Sirerol-piquer, Kristy Favell, José Manuel Morante-redolat, Philip A. Barker, Ana Ayerdi-izquierdo, Vicente Herranz-pérez, Jordi Pérez-turAbstract:Autosomal dominant lateral temporal epilepsy (ADTLE) is a partial epilepsy caused by mutations in LGI1, a multidomain protein of unknown function. To begin to understand the biological function of LGI1, we have determined its pattern of glycosylation, subcellular expression and capacity for secretion. LGI1 is expressed as two different isoforms in the brain, and we show that the long isoform is a secreted protein, whereas the short isoform is retained in an intracellular pool. ADLTE-related mutants of the long form are defective for secretion and are retained in the endoplasmic reticulum and Golgi complex. Finally, we show that normal secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells. We propose that LGI1 is a secreted factor important for neuronal development and that ADTLE is a disease that results from the loss of regulation in the protein available either extracellular or intracellularly.
Stéphanie Baulac - One of the best experts on this subject based on the ideXlab platform.
-
The Nogo Receptor Ligand LGI1 Regulates Synapse Number and Synaptic Activity in Hippocampal and Cortical Neurons.
eNeuro, 2018Co-Authors: Rhalena A. Thomas, Stéphanie Baulac, Julien Gibon, Carol X.-q. Chen, Sabrina Chierzi, Vincent G. Soubannier, Philippe Séguéla, Keith K. Murai, Philip A. BarkerAbstract:Leucine-rich glioma-inactivated protein 1 (LGI1) is a secreted neuronal protein and a Nogo receptor 1 (NgR1) ligand. Mutations in LGI1 in humans causes autosomal dominant lateral temporal lobe epilepsy and homozygous deletion of LGI1 in mice results in severe epileptic seizures that cause early postnatal death. NgR1 plays an important role in the development of CNS synapses and circuitry by limiting plasticity in the adult cortex via the activation of RhoA. These relationships and functions prompted us to examine the effect of LGI1 on synapse formation in vitro and in vivo. We report that application of LGI1 increases synaptic density in neuronal culture and that LGI1 null hippocampus has fewer dendritic mushroom spines than in wild-type (WT) littermates. Further, our electrophysiological investigations demonstrate that LGI1 null hippocampal neurons possess fewer and weaker synapses. RhoA activity is significantly increased in cortical cultures derived from LGI1 null mice and using a reconstituted system; we show directly that LGI1 antagonizes NgR1-tumor necrosis factor receptor orphan Y (TROY) signaling. Our data suggests that LGI1 enhances synapse formation in cortical and hippocampal neurons by reducing NgR1 signaling.
-
LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development
Scientific reports, 2016Co-Authors: Morgane Boillot, Stéphanie Baulac, Eric Leguern, Chun-yao Lee, Camille Allene, Nathalie RouachAbstract:The secreted leucine-rich glioma inactivated 1 (LGI1) protein is an important actor for human seizures of both genetic and autoimmune etiology: mutations in LGI1 cause inherited temporal lobe epilepsy, while LGI1 is involved in antibody-mediated encephalitis. Remarkably, LGI1-deficient (LGI1(-/-)) mice recapitulate the epileptic disorder and display early-onset spontaneous seizures. To understand how LGI1-deficiency leads to seizures during postnatal development, we here investigated the early functional and structural defects occurring before seizure onset in LGI1(-/-) mice. We found an increased excitatory synaptic transmission in hippocampal slices from LGI1(-/-) mice. No structural alteration in the morphology of pyramidal cell dendrites and synapses was observed at this stage, indicating that LGI1-deficiency is unlikely to trigger early developmental abnormalities. Consistent with the presynaptic subcellular localization of the protein, LGI1-deficiency caused presynaptic defects, with no alteration in postsynaptic AMPA receptor activity in LGI1-/- pyramidal cells before seizure onset. Presynaptic dysfunction led to increased synaptic glutamate levels, which were associated with hyperexcitable neuronal networks. Altogether, these data show that LGI1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development. We therefore here reveal that increased presynaptic glutamate release is a key early event resulting from LGI1-deficiency, which likely contributes to epileptogenesis.
-
A RAT MODEL FOR LGI1-RELATED EPILEPSIES
Human molecular genetics, 2012Co-Authors: Stéphanie Baulac, Saeko Ishida, Tomoji Mashimo, Morgane Boillot, Naohiro Fumoto, Mitsuru Kuwamura, Yukihiro Ohno, Akiko Takizawa, Toshihiro Aoto, Masatsugu UedaAbstract:Mutations of the leucine-rich glioma-inactivated 1 (LGI1) gene cause an autosomal dominant partial epilepsy with auditory features also known as autosomal-dominant lateral temporal lobe epilepsy. LGI1 is also the main antigen present in sera and cerebrospinal fluids of patients with limbic encephalitis and seizures, highlighting its importance in a spectrum of epileptic disorders. LGI1 encodes a neuronal secreted protein, whose brain function is still poorly understood. Here, we generated, by ENU (N-ethyl-N-nitrosourea) mutagenesis, LGI1-mutant rats carrying a missense mutation (L385R). We found that the L385R mutation prevents the secretion of LGI1 protein by COS7 transfected cells. However, the L385R-LGI1 protein was found at low levels in the brains and cultured neurons of LGI1-mutant rats, suggesting that mutant protein may be destabilized in vivo. Studies on the behavioral phenotype and intracranial electroencephalographic signals from LGI1-mutant rats recalled several features of the human genetic disorder. We show that homozygous LGI1-mutant rats (LGI1 L385R/L385R ) generated early-onset spontaneous epileptic seizures from P10 and died prematurely. Heterozygous LGI1-/mutant rats (Lgi 1+/L385R ) were more susceptible to sound-induced, generalized tonic-clonic seizures than control rats. Audiogenic seizures were suppressed by antiepileptic drugs such as carbamazepine, phenytoin and levetiracetam, which are commonly used to treat partial seizures, but not by the prototypic absence seizure drug, ethosuximide. Our findings provide the first rat model with a missense mutation in LGI1 gene, an original model complementary to knockout mice. This study revealed that LGI1 disease-causing missense mutations might cause a depletion of the protein in neurons, and not only a failure of LGI1 secretion.
-
Epilepsy Gene LGI1 Regulates Postnatal Developmental Remodeling of Retinogeniculate Synapses
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012Co-Authors: Yu-dong Zhou, Stéphanie Baulac, Dawei Zhang, Ekim Ozkaynak, Xuan Wang, Ekkehard M. Kasper, Eric Leguern, Matthew P. AndersonAbstract:Retinogeniculate connections undergo postnatal refinement in the developing visual system. Here we report that non-ion channel epilepsy gene LGI1 (leucine-rich glioma-inactivated), mutated in human autosomal dominant lateral temporal lobe epilepsy (ADLTE), regulates postnatal pruning of retinal axons in visual relay thalamus. By introducing an ADLTE-associated truncated mutant LGI1 (836delC) or excess full-length LGI1 into transgenic mice, we found that mutant LGI1 blocks, whereas excess LGI1 accelerates, retinogeniculate axon pruning. The normal postnatal single fiber strengthening was arrested by mutant LGI1 and, contrastingly, was enhanced by excess wild-type LGI1. The maximum response of the retinogeniculate synapses, conversely, remained the same in mature LGI1 transgenic mice, indicating that mutant LGI1 blocks, whereas excess wild-type LGI1 promotes, weak axon fiber elimination. Heterozygous deletion of the LGI1 gene, as found in ADLTE patients, inhibited postnatal retinogeniculate synapse elimination, an effect similar to the ADLTE truncated mutant LGI1. The results identify sensory axon remodeling defects in a sensory aura-associated human epilepsy disorder.
-
Two novel epilepsy-linked mutations leading to a loss of function of LGI1.
Archives of neurology, 2007Co-Authors: Elodie Chabrol, Eric Leguern, Cyprian Popescu, Isabelle Gourfinkel-an, Oriane Trouillard, Christel Depienne, Kristen Senechal, Michel Baulac, Stéphanie BaulacAbstract:BACKGROUND: Mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene have been implicated in autosomal dominant lateral temporal epilepsy. OBJECTIVE: To describe the clinical and genetic findings in 2 families with autosomal dominant lateral temporal epilepsy and the functional consequences of 2 novel mutations in LGI1. DESIGN: Clinical, genetic, and functional investigations. SETTING: University hospital. Patients Two French families with autosomal dominant lateral temporal epilepsy. Main Outcome Measure Mutation analysis. RESULTS: Two novel disease-linked mutations, p.Leu232Pro and c.431 + 1G>A, were identified in LGI1. We demonstrated that the c.431 + 1G>A mutation causes the deletion of exons 3 and 4 of the LGI1 transcript and showed that the p.Leu232Pro mutation dramatically decreases secretion of the mutant protein by mammalian cells. CONCLUSION: Our data indicate that LGI1 is a secreted protein and suggest that LGI1-related epilepsy results from a loss of function.