Induction of Anti-agrin Antibodies Causes Myasthenia Gravis in Mice.

Neuroscience

Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA; Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland VAMC, Cleveland, OH, USA. Electronic address:

Published: March 2018

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction (NMJ). Most cases of MG are caused by autoantibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4). Recent studies have identified anti-agrin antibodies in MG patients lacking these three antibodies (i.e., triple negative MG). Agrin is a basal lamina protein that has two isoforms. Neural agrin (N-agrin) binds to LRP4 to activate MuSK to induce AChR clusters and is thus critical for NMJ formation. We demonstrate that mice immunized with N-agrin showed MG-associated symptoms including muscle weakness, fragmented and distorted NMJs. These effects were not observed in mice injected with muscle agrin (M-agrin), an isoform that is inactive in inducing AChR clusters. Treatment with anti-N-agrin, but not anti-M-agrin, antibodies reduced agrin-induced AChR clusters in muscle cells. Together, these observations suggest that agrin antibodies may be play a role in MG pathogenesis.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942223PMC
http://dx.doi.org/10.1016/j.neuroscience.2018.01.015DOI Listing

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