Trans-synaptic LGI1–ADAM22–MAGUK in AMPA and NMDA receptor regulation

Fukata, Yuko; Hirano, Yoko; Miyazaki, Yuri; Yokoi, Norihiko; Fukata, Masaki

doi:10.1016/j.neuropharm.2021.108628

Cited by 26 publications

(25 citation statements)

References 72 publications

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“…[1][2][3][4] It has been suggested that LGI1 plays an essential role in the formation of a functional trans-synaptic complex linking presynaptic Kv1 channels to postsynaptic AMPA/NMDA receptors and PSD95 through interaction with ADAM 22/23 . 2,5,6,7 LGI1 owes its name to its downregulated expression in malignant gliomas, its first involvement in a human disease. 8 Point mutations in LGI1, the majority of which lead to an inhibition of LGI1 secretion, [9][10][11] have been linked to inherited, autosomal-dominant lateral temporal lobe epilepsy (ADLTE) 12,13 and neuronal hyperexcitability.…”

Section: Introductionmentioning

confidence: 99%

“…LGI1 interaction may account for the phenotype associated with these human LGI1 mutations. 7 In mice, LGI1 deletion results in lethal seizures accompanied by a reduction in the AMPA / NMDA receptor ratio and a decrease in AMPA receptor-mediated synaptic transmission. 5,6,19 However, whether these modifications account for the observed neuronal hyperexcitability is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1

Ramírez‐Franco

Debreux

Extrémet

et al. 2022

Brain

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Autoantibodies against leucine-rich glioma-inactivated 1 occur in patients with encephalitis who present with frequent focal seizures and a pattern of amnesia consistent with focal hippocampal damage. To investigate whether the cellular and subcellular distribution of LGI1 may explain the localisation of these features, and hence gain broader insights into LGI1’s neurobiology, we analysed the detailed localisation of LGI1, and the diversity of its protein interactome, in mouse brains using patients-derived recombinant monoclonal LGI1-antibodies. Combined immunofluorescence and mass spectrometry analyses showed that LGI1 is enriched in excitatory and inhibitory synaptic contact sites, most densely within CA3 regions of the hippocampus. LGI1 is secreted in both neuronal somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic and astro-microglial protein complexes. Proteomic data support the presence of LGI1/Kv1/MAGUK complexes, but did not reveal LGI1 complexes with postsynaptic glutamate receptors. Our results extend our understanding of regional, cellular and subcellular LGI1 expression profiles and reveal novel LGI1-associated complexes, thus providing insights into the complex biology of LGI1 and its relationship to seizures and memory loss.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1

Ramírez‐Franco

Debreux

Extrémet

et al. 2022

Brain

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“…Defects in LGI1 , ADAM22 and ADAM23 have all been genetically linked to epilepsy, indicating the physiological relevance of this complex. 16 Knock-out mice for Lgi1 , 5 , 17 , 18 Adam22 19 and Adam23 20 exhibit lethal seizures in early postnatal life. In humans, heterozygous pathogenic variants in LGI1 have been associated with autosomal dominant lateral temporal lobe epilepsy (ADLTE; OMIM #600512).…”

Section: Introductionmentioning

confidence: 99%

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Knoop

Maroofian

Fukata

et al. 2022

Brain

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Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

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“…Through the latter it interacts with the ectodomains of ADAM22, 23 and 11 which are catalytically-inactive members of the ADAMs family of metalloproteases [80] [19] [65] [56]. It has been suggested that LGI1 plays an essential role in the formation of a functional trans-synaptic complex linking presynaptic Kv1 channels to postsynaptic AMPA/NMDA receptors and PSD95 through interaction with ADAM 22/23 [19] [21] [46] [20].…”

Section: Introductionmentioning

confidence: 99%

“…Point mutations in LGI1, the majority of which lead to an inhibition of LGI1 secretion [69] [52] [45], have been linked to inherited, autosomal-dominant lateral temporal lobe epilepsy (ADLTE) [51] [34] and neuronal hyperexcitability [83] [5] [87]. In ADLTE, the few secreted LGI1 mutants show impaired ADAM22 binding [12] [81], suggesting that hypofunction of the ADAM22-LGI1 interaction may account for the phenotype associated with these human LGI1 mutations [20]. In mice, LGI1 deletion results in lethal seizures accompanied by a reduction in the AMPA / NMDA receptor ratio and a decrease in AMPA receptor-mediated synaptic transmission [21] [22] [46].…”

Section: Introductionmentioning

confidence: 99%

Patient-derived recombinant autoantibodies reveal the subcellular neuroglial distribution and heterogeneous interactome of leucine-rich glioma-inactivated 1

Ramírez‐Franco

Debreux

Extrémet

et al. 2022

Preprint

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Autoantibodies against leucine-rich glioma-inactivated 1 (LGI1) occur in patients with encephalitis who present with frequent focal seizures and a pattern of amnesia consistent with focal hippocampal damage. To investigate whether the cellular and subcellular distribution of LGI1 may explain the localisation of these features, and gain broader insights into LGI1 neurobiology, we analysed the detailed localisation of LGI1, and the diversity of its protein interactome, in mouse brains using recombinant monoclonal LGI1-antibodies derived from encephalitis patients. Combined immunofluorescence and mass spectrometry analyses showed that LGI1 is enriched in excitatory and inhibitory synaptic contact sites, most densely within CA3 regions of the hippocampus. LGI1 is secreted in both neuronal somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic and astro-microglial protein complexes. Proteomic data support the hypothesis that destabilization of Kv1 / MAGUK complexes by autoantibodies could promote excitability, but did not reveal LGI1 complexes with postsynaptic glutamate receptors. Our results extend our understanding of regional, cellular and subcellular LGI1 expression profiles and reveal novel LGI1-associated complexes, thus providing insights into the complex biology of LGI1 and its relationship to seizures and memory loss.

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Trans-synaptic LGI1–ADAM22–MAGUK in AMPA and NMDA receptor regulation

Cited by 26 publications

References 72 publications

Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1

Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Patient-derived recombinant autoantibodies reveal the subcellular neuroglial distribution and heterogeneous interactome of leucine-rich glioma-inactivated 1

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