Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction.
Adult
Aged
Animals
Autoantibodies
/ immunology
Autoantigens
/ immunology
Behavior, Animal
/ drug effects
Encephalomyelitis
/ immunology
Epitopes, B-Lymphocyte
/ immunology
Female
Humans
Male
Middle Aged
Muscle Rigidity
/ immunology
Receptors, Glycine
/ immunology
Stiff-Person Syndrome
/ immunology
Zebrafish
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
17
03
2019
revised:
23
06
2020
accepted:
23
06
2020
pubmed:
27
6
2020
medline:
5
1
2021
entrez:
27
6
2020
Statut:
ppublish
Résumé
Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.
Substances chimiques
Autoantibodies
0
Autoantigens
0
Epitopes, B-Lymphocyte
0
Receptors, Glycine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
544-561Informations de copyright
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Références
Ameli R, Snow J, Rakocevic G, Dalakas MC. A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 2005;64:1961-1963.
Balint B, Bhatia KP. Stiff person syndrome and other immune-mediated movement disorders-new insights. Curr Opin Neurol 2016;29:496-506.
Henningsen P, Meinck HM. Specific phobia is a frequent non-motor feature in stiff man syndrome. J Neurol Neurosurg Psychiatry 2003;74:462-465.
Carvajal-Gonzalez A, Leite MI, Waters P, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 2014;137(pt 8):2178-2192.
Hutchinson M, Waters P, McHugh J, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008;71:1291-1292.
McKeon A, Martinez-Hernandez E, Lancaster E, et al. Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol 2013;70:44-50.
Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017;97:839-887.
Bode A, Lynch JW. The impact of human hyperekplexia mutations on glycine receptor structure and function. Mol Brain 2014;7:2.
Baizabal-Carvallo JF, Jankovic J. Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatry 2015;86:840-848.
Geis C, Beck M, Jablonka S, et al. Stiff person syndrome associated anti-amphiphysin antibodies reduce GABA associated [ca(2+)]i rise in embryonic motoneurons. Neurobiol Dis 2009;36:191-199.
Meinck HM, Thompson PD. Stiff man syndrome and related conditions. Mov Disord 2002;17:853-866.
Sommer C, Weishaupt A, Brinkhoff J, et al. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005;365:1406-1411.
Alexopoulos H, Akrivou S, Dalakas MC. Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders. Neurology 2013;81:1962-1964.
Crisp SJ, Dixon CL, Jacobson L, et al. Glycine receptor autoantibodies disrupt inhibitory neurotransmission. Brain 2019;142:3398-3410.
Malosio ML, Marqueze-Pouey B, Kuhse J, Betz H. Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain. EMBO J 1991;10:2401-2409.
Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 2004;84:1051-1095.
Lynch JW. Native glycine receptor subtypes and their physiological roles. Neuropharmacology 2009;56:303-309.
Kneussel M, Betz H. Clustering of inhibitory neurotransmitter receptors at developing postsynaptic sites: the membrane activation model. Trends Neurosci 2000;23:429-435.
Du J, Lu W, Wu S, et al. Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature 2015;526:224-229.
Huang X, Chen H, Michelsen K, et al. Crystal structure of human glycine receptor-alpha3 bound to antagonist strychnine. Nature 2015;526:277-280.
Huang X, Shaffer PL, Ayube S, et al. Crystal structures of human glycine receptor alpha3 bound to a novel class of analgesic potentiators. Nat Struct Mol Biol 2017;24:108-113.
Doppler K, Schleyer B, Geis C, et al. Lockjaw in stiff-person syndrome with autoantibodies against glycine receptors. Neurol Neuroimmunol Neuroinflamm 2016;3:e186.
Buchwald B, Weishaupt A, Toyka KV, Dudel J. Pre- and postsynaptic blockade of neuromuscular transmission by Miller-Fisher syndrome IgG at mouse motor nerve terminals. Eur J Neurosci 1998;10:281-290.
Fuhrmann JC, Kins S, Rostaing P, et al. Gephyrin interacts with dynein light chains 1 and 2, components of motor protein complexes. J Neurosci 2002;22:5393-5402.
Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54:1044-1054.
Chen C, Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol 1987;7:2745-2752.
Breitinger U, Breitinger HG, Bauer F, et al. Conserved high affinity ligand binding and membrane association in the native and refolded extracellular domain of the human glycine receptor alpha1-subunit. J Biol Chem 2004;279:1627-1636.
Sontheimer H, Becker CM, Pritchett DB, et al. Functional chloride channels by mammalian cell expression of rat glycine receptor subunit. Neuron 1989;2:1491-1497.
Schaefer N, Berger A, van Brederode J, et al. Disruption of a structurally important extracellular element in the glycine receptor leads to decreased synaptic integration and signaling resulting in severe startle disease. J Neurosci 2017;37:7948-7961.
Schindelin J, Rueden CT, Hiner MC, Eliceiri KW. The ImageJ ecosystem: an open platform for biomedical image analysis. Mol Reprod Dev 2015;82:518-529.
Ogino K, Yamada K, Nishioka T, et al. Phosphorylation of gephyrin in zebrafish Mauthner cells governs glycine receptor clustering and behavioral desensitization to sound. J Neurosci 2019;39:8988-8997.
Deckert J, Weber H, Villmann C, et al. GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder. Mol Psychiatry 2017;22:1431-1439.
Schaefer N, Kluck CJ, Price KL, et al. Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia. J Neurosci 2015;35:422-437.
Spurny R, Debaveye S, Farinha A, et al. Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the alpha7 nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A 2015;112:E2543-E2552.
Budick SA, O'Malley DM. Locomotor repertoire of the larval zebrafish: swimming, turning and prey capture. J Exp Biol 2000;203(pt 17:2565-2579.
Hirata H, Ogino K, Yamada K, et al. Defective escape behavior in DEAH-box RNA helicase mutants improved by restoring glycine receptor expression. J Neurosci 2013;33:14638-14644.
Saint-Amant L, Drapeau P. Time course of the development of motor behaviors in the zebrafish embryo. J Neurobiol 1998;37:622-632.
Balint B, Vincent A, Meinck HM, et al. Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology. Brain 2018;141:13-36.
Crisp SJ, Balint B, Vincent A. Redefining progressive encephalomyelitis with rigidity and myoclonus after the discovery of antibodies to glycine receptors. Curr Opin Neurol 2017;30:310-316.
Borellini L, Lanfranconi S, Bonato S, et al. Progressive encephalomyelitis with rigidity and myoclonus associated with anti-GlyR antibodies and Hodgkin's lymphoma: a case report. Front Neurol 2017;8:401.
Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 2013;54:1028-1035.
De Blauwe SN, Santens P, Vanopdenbosch LJ. Anti-glycine receptor antibody mediated progressive encephalomyelitis with rigidity and myoclonus associated with breast cancer. Case Rep Neurol Med 2013;2013:589154.
Zuliani L, Ferlazzo E, Andrigo C, et al. Glycine receptor antibodies in 2 cases of new, adult-onset epilepsy. Neurol Neuroimmunol Neuroinflamm 2014;1:e16.
Castillo-Gomez E, Oliveira B, Tapken D, et al. All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class. Mol Psychiatry 2017;22:1776-1784.
Atak S, Langlhofer G, Schaefer N, et al. Disturbances of ligand potency and enhanced degradation of the human glycine receptor at affected positions G160 and T162 originally identified in patients suffering from hyperekplexia. Front Molec Neurosci 2015;8:79.
Villmann C, Oertel J, Melzer N, Becker CM. Recessive hyperekplexia mutations of the glycine receptor alpha1 subunit affect cell surface integration and stability. J Neurochem 2009;111:837-847.
Bode A, Wood SE, Mullins JG, et al. New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms. J Biol Chem 2013;288:33745-33759.
Chung SK, Vanbellinghen JF, Mullins JG, et al. Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia. J Neurosci 2010;30:9612-9620.
Saul B, Kuner T, Sobetzko D, et al. Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating. J Neurosci 1999;19:869-877.
Zhang Y, Bode A, Nguyen B, et al. Investigating the mechanism by which gain-of-function mutations to the alpha1 glycine receptor cause hyperekplexia. J Biol Chem 2016;291:15332-15341.
Ganser LR, Yan Q, James VM, et al. Distinct phenotypes in zebrafish models of human startle disease. Neurobiol Dis 2013;60:139-151.
Hirata H, Saint-Amant L, Downes GB, et al. Zebrafish bandoneon mutants display behavioral defects due to a mutation in the glycine receptor beta-subunit. Proc Natl Acad Sci U S A 2005;102:8345-8350.
Leacock S, Syed P, James VM, et al. Structure/function studies of the α4 subunit reveal evolutionary loss of a GlyR subtype involved in startle and escape responses. Front Mol Neurosci 2018;11:23.
Stengel H, Vural A, Brunder AM, et al. Anti-pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy. Neurol Neuroimmunol Neuroinflamm 2019;6:e603.