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Lambert-Eaton myasthenic syndrome: mouse passive-transfer model illuminates disease pathology and facilitates testing therapeutic leads.

Authors
  • Meriney, Stephen D1
  • Tarr, Tyler B1
  • Ojala, Kristine S1
  • Wu, Man1
  • Li, Yizhi1
  • Lacomis, David2
  • Garcia-Ocaña, Adolfo3
  • Liang, Mary4
  • Valdomir, Guillermo4
  • Wipf, Peter4
  • 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • 2 Division of Neuromuscular Diseases, Departments of Neurology and Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
  • 3 Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania.
Type
Published Article
Journal
Annals of the New York Academy of Sciences
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jan 01, 2018
Volume
1412
Issue
1
Pages
73–81
Identifiers
DOI: 10.1111/nyas.13512
PMID: 29125190
Source
Medline
Keywords
License
Unknown

Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2-4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low. LEMS further reduces this low probability such that transmission is no longer effective at triggering a muscle contraction. The LEMS-mediated attack reduces the number of presynaptic calcium channels, disorganizes transmitter release sites, and results in the homeostatic upregulation of other calcium channel types. Symptomatic treatment is focused on increasing the probability of release from dysfunctional release sites. Current treatment uses the potassium channel blocker 3,4-diaminopyridine (DAP) to broaden the presynaptic action potential, providing more time for calcium channels to open. Current research is focused on testing new calcium channel gating modifiers that work synergistically with DAP.

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