Development of Animal Models of Anti-MuSK Myasthenia

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DESCRIPTION (provided by applicant): Anti-muscle-specific kinase (MuSK) myasthenia (AMM) is a newly-described disease of neuromuscular transmission characterized by fatigable weakness, muscle wasting and circulating antibodies (Abs) to MuSK, a transmembrane receptor kinase crucial to the formation of this synapse. AMM differs from myasthenia gravis (MG) in its severity, the more focal nature of the weakness and the associated muscle wasting. Remarkably little is known concerning its pathogenesis or etiology, including whether there is an accompanying cellular immune response to MuSK and what mechanisms underlie the abnormal neuromuscular transmission and muscle wasting. The treatment of this disease is nearly completely unknown. Current clinical practice is to use the treatment protocols developed for (seropositive) MG. However, data have accumulated demonstrating that many of these treatments, e.g. cholinesterase inhibitors, thymectomy and immunoglobulin infusion, are minimally effective. Our overall goal is to develop more specific and effective treatments of AMM. To accomplish this, we have produced an animal model of AMM in Lewis rats, termed experimental AMM (EAMM), to serve as a platform for analysis of the pathogenic mechanisms underlying the human disease, including the mechanisms active at the neuromuscular junction (NMJ) and the mechanisms underlying the immune attack on this synapse. The model disease, which is induced by a single injection of the MuSK 60 isoform of the protein is quite severe, resulting in fatigable weakness and muscle wasting leading to death within 27 days, along with severe disruption of both the postsynaptic and presynaptic components of the NMJ. The proposed studies will address the hypothesis that AMM is an Ab-mediated disease and that the MuSK Abs alter the function of MuSK at the mature NMJ, thereby inducing the weakness and muscle wasting that are characteristic of this disease. A corollary of that hypothesis is that MuSK, in addition to its known role in the developing NMJ, plays an important role in the maintenance of the mature synapse. The first specific aim involves the analysis of the pathogenic mechanisms operative at the NMJ in EAMM through clinical, electrophysiologic and morphologic studies of the NMJ, focusing on the signal transduction pathways activated by MuSK. The second specific aim analyzes the nature of the autoimmune response in EAMM by assessing both the Ab and T cell responses to MuSK in these animals, along with studies of passive transfer of the disease with both immunoglobulin derived from EAMM serum and lymphocytes from EAMM spleens and lymph nodes. PUBLIC HEALTH RELEVANCE: Relevance: Remarkably little is known concerning the pathogenesis or etiology of anti-muscle-specific kinase (MuSK) myasthenia (AMM), including whether the MuSK Abs are, in fact, pathogenic, whether there is an accompanying cellular immune response and what mechanisms underlie the abnormal neuromuscular transmission and muscle wasting. The treatment of this disease is also nearly completely unknown. This project will provide the means for determining the underlying mechanisms in AMM in order to identify new treatments and provide an animal model for testing these treatments.