Human CASPR2 Antibodies Reversibly Alter Memory and the CASPR2 Protein Complex.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
revised:
02
03
2022
received:
28
12
2021
accepted:
04
03
2022
pubmed:
8
3
2022
medline:
18
5
2022
entrez:
7
3
2022
Statut:
ppublish
Résumé
The encephalitis associated with antibodies against contactin-associated proteinlike 2 (CASPR2) is presumably antibody-mediated, but the antibody effects and whether they cause behavioral alterations are not well known. Here, we used a mouse model of patients' immunoglobulin G (IgG) transfer and super-resolution microscopy to demonstrate the antibody pathogenicity. IgG from patients with anti-CASPR2 encephalitis or healthy controls was infused into the cerebroventricular system of mice. The levels and colocalization of CASPR2 with transient axonal glycoprotein 1 (TAG1) were determined with stimulated emission depletion microscopy (40-70μm lateral resolution). Hippocampal clusters of Kv1.1 voltage-gated potassium channels (VGKCs) and GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were quantified with confocal microscopy. Behavioral alterations were assessed with standard behavioral paradigms. Cultured neurons were used to determine the levels of intracellular CASPR2 and TAG1 after exposure to patients' IgG. Infusion of patients' IgG, but not controls' IgG, caused memory impairment along with hippocampal reduction of surface CASPR2 clusters and decreased CASPR2/TAG1 colocalization. In cultured neurons, patients' IgG led to an increase of intracellular CASPR2 without affecting TAG1, suggesting selective CASPR2 internalization. Additionally, mice infused with patients' IgG showed decreased levels of Kv1.1 and GluA1 (two CASPR2-regulated proteins). All these alterations and the memory deficit reverted to normal after removing patients' IgG. IgG from patients with anti-CASPR2 encephalitis causes reversible memory impairment, inhibits the interaction of CASPR2/TAG1, and decreases the levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the postulates of antibody-mediated disease and provide a biological basis for antibody-removing treatment approaches. ANN NEUROL 2022;91:801-813.
Substances chimiques
Autoantibodies
0
CNTNAP2 protein, human
0
CNTNAP2 protein, mouse
0
Contactin 2
0
Immunoglobulin G
0
Membrane Proteins
0
Nerve Tissue Proteins
0
Potassium Channels, Voltage-Gated
0
anti-CASPR2 autoantibody
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
801-813Informations de copyright
© 2022 American Neurological Association.
Références
van Sonderen A, Arino H, Petit-Pedrol M, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology 2016;87:521-528.
Saint-Martin M, Joubert B, Pellier-Monnin V, et al. Contactin-associated protein-like 2, a protein of the neurexin family involved in several human diseases. Eur J Neurosci 2018;48:1906-1923.
Varea O, Martin-de-Saavedra MD, Kopeikina KJ, et al. Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons. Proc Natl Acad Sci U S A 2015;112:6176-6181.
Savvaki M, Theodorakis K, Zoupi L, et al. The expression of TAG-1 in glial cells is sufficient for the formation of the juxtaparanodal complex and the phenotypic rescue of tag-1 homozygous mutants in the CNS. J Neurosci 2010;30:13943-13954.
Fernandes D, Santos SD, Coutinho E, et al. Disrupted AMPA receptor function upon genetic- or antibody-mediated loss of autism-associated CASPR2. Cereb Cortex 2019;29:4919-4931.
Joubert B, Saint-Martin M, Noraz N, et al. Characterization of a subtype of autoimmune encephalitis with anti-contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures. JAMA Neurol 2016;73:1115-1124.
Patterson KR, Dalmau J, Lancaster E. Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Ann Neurol 2018;83:40-51.
Saint-Martin M, Pieters A, Dechelotte B, et al. Impact of anti-CASPR2 autoantibodies from patients with autoimmune encephalitis on CASPR2/TAG-1 interaction and Kv1 expression. J Autoimmun 2019;103:102284.
Giannoccaro MP, Menassa DA, Jacobson L, et al. Behaviour and neuropathology in mice injected with human contactin-associated protein 2 antibodies. Brain 2019;142:2000-2012.
Dawes JM, Weir GA, Middleton SJ, et al. Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability. Neuron 2018;97:806-822.e10.
Pinatel D, Hivert B, Saint-Martin M, et al. The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons. J Cell Sci 2017;130:2209-2220.
Balint S, Verdeny VI, Sandoval AA, Lakadamyali M. Correlative live-cell and superresolution microscopy reveals cargo transport dynamics at microtubule intersections. Proc Natl Acad Sci U S A 2013;110:3375-3380.
Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391-404.
Gresa-Arribas N, Planaguma J, Petit-Pedrol M, et al. Human neurexin-3alpha antibodies associate with encephalitis and alter synapse development. Neurology 2016;86:2235-2242.
Sabater L, Planaguma J, Dalmau J, Graus F. Cellular investigations with human antibodies associated with the anti-IgLON5 syndrome. J Neuroinflammation 2016;13:226.
Petit-Pedrol M, Sell J, Planaguma J, et al. LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain 2018;141:3144-3159.
Planaguma J, Leypoldt F, Mannara F, et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 2015;138:94-109.
Kilkenny C, Browne WJ, Cuthill IC, et al. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 2010;8:e1000412.
Planaguma J, Haselmann H, Mannara F, et al. Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity. Ann Neurol 2016;80:388-400.
Carceles-Cordon M, Mannara F, Aguilar E, et al. NMDAR antibodies alter dopamine receptors and cause psychotic behavior in mice. Ann Neurol 2020;88:603-613.
Niemir N, Rouviere L, Besse A, et al. Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in Sandhoff disease mice. Hum Mol Genet 2018;27:954-968.
Castellanos A, Pujol-Coma A, Andres-Bilbe A, et al. TRESK background K(+) channel deletion selectively uncovers enhanced mechanical and cold sensitivity. J Physiol 2020;598:1017-1038.
Wertman V, Gromova A, La Spada AR, Cortes CJ. Low-cost gait analysis for behavioral phenotyping of mouse models of neuromuscular disease. J Vis Exp 2019;(149):e59878. https://doi.org/10.3791/59878.
Murai T, Okuda S, Tanaka T, Ohta H. Characteristics of object location memory in mice: behavioral and pharmacological studies. Physiol Behav 2007;90:116-124.
Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol Today 1993;14:426-430.
Olsen AL, Lai Y, Dalmau J, et al. Caspr2 autoantibodies target multiple epitopes. Neurol Neuroimmunol Neuroinflamm 2015;2:e127.
Hara M, Martinez-Hernandez E, Arino H, et al. Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor. Neurology 2018;90:e1386-e1394.
Gleichman AJ, Spruce LA, Dalmau J, et al. Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain. J Neurosci 2012;32:11082-11094.
Sayyah M, Javad-Pour M, Ghazi-Khansari M. The bacterial endotoxin lipopolysaccharide enhances seizure susceptibility in mice: involvement of proinflammatory factors: nitric oxide and prostaglandins. Neuroscience 2003;122:1073-1080.
Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010;30:5866-5875.
Poliak S, Salomon D, Elhanany H, et al. Juxtaparanodal clustering of shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 2003;162:1149-1160.
Traka M, Goutebroze L, Denisenko N, et al. Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol 2003;162:1161-1172.
Ohkawa T, Fukata Y, Yamasaki M, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013;33:18161-18174.
Ramberger M, Berretta A, Tan JMM, et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 2020;143:1731-1745.