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Neuroforum

Organ der Neurowissenschaftlichen Gesellschaft

Editor-in-Chief: Wahle, Petra


CiteScore 2018: 0.11

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Volume 25, Issue 2

Issues

Autoantibodies Against NMDA Receptors – Janus-Faced Molecules?

Prof. Dr. Dr. Hannelore Ehrenreich / Prof. Dr. Michael Hollmann
  • Corresponding author
  • Department of Biochemistry I – Receptor Biochemistry Ruhr University Bochum phone: +49 234 32-24225 Bochum Germany
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/ Justus B. H. Wilke
  • Corresponding author
  • Department of Biochemistry I – Receptor Biochemistry Ruhr University Bochum Bochum Germany
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  • Other articles by this author:
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Published Online: 2019-06-04 | DOI: https://doi.org/10.1515/nf-2018-0025

Zusammenfassung

Wie schon der römische Gott des Anfangs und des Endes, Janus, könnten auch Antikörper (AB) gegen N-Methyl-D-aspartatrezeptoren (NMDAR) zwei Gesichter besitzen und duale Effekte vermitteln, wenn sie Zugang zum zentralen Nervensystem erhalten. In den letzten Jahren rückten Autoantikörper gegen die obligatorische NMDAR-Untereinheit GluN1 zunehmend in den Fokus von Ärzten, da GuN1-Antikörper (GluN1-AB) in der Cerebrospinalflüssigkeit als diagnostisches Kriterium für die sogenannte anti-NMDAR-Enzephalitis genutzt werden. Jedoch sind GluN1-AB auch im Blutserum vieler gesunder Menschen vorhanden. Mittlerweile haben zahlreiche Studien die Häufigkeit, die Epitope und den molekularen Wirkmechanismus von GluN1-AB verschiedener Ursprünge und Immunglobulinklassen analysiert. Interessanterweise vermitteln GluN1-AB die Quervernetzung und Internalisierung von NMDAR. In diesem Übersichtsartikel werden wir vorstellen, wie GluN1-AB Neurone potentiell vor den neurotoxischen Prozessen einer Übererregung der exzitatorischen Neurotransmission schützen, jedoch ebenfalls psychose-ähnliche Zustände auslösen können. Zusätzlich werden wir die Pathogenität von GluN1-AB mit Bezug auf entzündliche Prozesse genauer betrachten.

Abstract

Just like the two-faced Roman god of the beginning and the end, Janus, autoantibodies against N-methyl-D-aspartate receptors (NMDAR) have dualistic effects on the human brain. In recent years, autoantibodies against the GluN1 subunit of NMDAR gained attention by physicians world-wide as a diagnostic criterion for the so-called anti-NMDAR encephalitis. Seemingly contradictory was the subsequent identification of GluN1 autoantibodies (GluN1-AB) in healthy subjects. By now, many studies analysed the abundance of GluN1-AB, their immunoglobulin classes, epitopes, and mode of action. Interestingly, GluN1-AB exert their effects by cross-linking NMDAR, which triggers their internalisation. In this review we will discuss how the resulting decrease of surface NMDAR has the potential to protect neurons from neurotoxic events during states of hyperexcitation while at the same time inducing psychosis-like symptoms upon access to the brain. Additionally, we will discuss the pathogenicity of GluN1-AB in the context of brain inflammation.

Abbreviations: AB, antibodies; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(s); BBB, blood-brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid; iGluR, ionotropic glutamate receptor(s); NMDAR, N-methyl-D-aspartate receptor(s)

Keywords: N-Methyl-D-aspartate receptor; anti-NMDAR encephalitis; NMDAR autoantibodies; GluN1 autoantibodies, ketamine-like syndrome

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About the article

Prof. Dr. Dr. Hannelore Ehrenreich

Hannelore Ehrenreich studied medicine and veterinary medicine in Hanover and Munich, Germany. In parallel to her clinical training in neurology and psychiatry (in Munich and Göttingen) she had several grant-funded research positions in the USA (with Dr. Anthony S. Fauci, NIAID, NIH, Bethesda, MD), England and the Philippines. She is professor of neurology and psychiatry, with teaching responsibilities at the Medical as well as the Psychological & Biological faculty of the Georg-August-University of Göttingen, Germany. Since 1995, she is Head of Clinical Neuroscience at the Max Planck Institute of Experimental Medicine, Göttingen. Her research area of interest is translational neuroscience with focus on: (1) Genetic and environmental underpinnings of neuropsychiatric diseases; (2) Endogenous neuroprotection and neuroregeneration as therapeutic strategies for patients: Research centering on the brain erythropoietin system and hypoxia; (3) Autoimmune and inflammatory processes contributing to neuropsychiatric phenotypes.

Prof. Dr. Michael Hollmann

Michael Hollmann studied biochemistry in Tübingen and received his PhD from the University of Tübingen for a project carried out at the Max Planck Institute of Biophysical Chemistry in Göttingen, under the supervision of Wilfried Seifert (1988). He spent six years (1988–1994) as a Postdoctoral Research Associate with the late Stephen F. Heinemann at the Salk Institute for Biological Studies in La Jolla, California, USA. He returned to Germany on a Heisenberg Fellowship and set up his independent research group at the Max Planck Institute for Experimental Medicine in Göttingen, where he received his Habilitation in Biochemistry from the Medical Faculty of the University of Göttingen in 1998. Since 1999 he has been a Full Professor of Biochemistry at the Ruhr University Bochum. His research interests encompass the structure, function, regulation, and modulation of ionotropic glutamate receptors, with a current focus on (1) glutamate receptor-interacting membrane proteins, (2) autoantibodies against glutamate receptors, and (3) plant glutamate-like receptors. For more information see www.ruhr-uni-bochum.de/bc1.

Justus B. H. Wilke

Justus Wilke studied biochemistry at the Ruhr University Bochum. For his master thesis he worked on NMDA receptors in the Receptor Biochemistry department of Michael Hollmann. After his graduation in September 2018 he joined the Clinical Neuroscience group of Hannelore Ehrenreich at the Max Planck Institute of Experimental Medicine in Göttingen. For his PhD he is investigating how autoantibodies against GluN1 modulate brain functions.


Published Online: 2019-06-04

Published in Print: 2019-05-27


Citation Information: Neuroforum, Volume 25, Issue 2, Pages 89–98, ISSN (Online) 2363-7013, ISSN (Print) 0947-0875, DOI: https://doi.org/10.1515/nf-2018-0025.

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