Role of Muscle Specific Kinase at the Adult Neuromuscular Junction

Abstract

Muscle Specific Kinase (MuSK) is a transmembrane tyrosine kinase essential for the formation and maintenance of the neuromuscular junction (NMJ). Effective neurotransmission at the NMJ depends upon clustering of AChRs on the postsynaptic membrane directly opposite the nerve terminal. MuSK forms the core of a signalling complex that can be activated by neural agrin, initiating complex intracellular signalling events that coordinate the clustering of AChRs and other synaptic proteins at the NMJ. Autoimmune myasthenia gravis (MG) is the most common disorder of the NMJ that causes impaired neuromuscular transmission and muscle weakness. Approximately 10% of MG patients have autoantibodies against MuSK. This thesis investigates the molecular mechanisms by which anti-MuSK autoantibodies cause myasthenia gravis. I show that repeated daily injections of anti-MuSK patient immunoglobulin G (IgG) into adult mice reduced endplate levels of several components of the MuSK signalling pathway, including MuSK, activated Src, phosphorylated AChR and rapsyn. This suggests that anti-MuSK patient antibodies cause synaptic failure by suppressing MuSK signalling pathway at the NMJ. Anti-MuSK IgG injection caused an accelerated loss of pre-existing AChRs from the endplate without a compensatory increase in the rate of incorporation of newly-synthesised replacement AChRs. Albuterol has been reported beneficial in treating several forms of congenital myasthenia. Using the mouse model I show that albuterol treatment reduced the degree of whole-body weakness and weight loss but without reversing myasthenic impairment to the structure and function of the NMJ. Given mine and other studies suggesting that AChR loss might be caused by reduced endplate expression or activity of MuSK I have examined the effect of supplementing expression of MuSK in myasthenic muscles. I provide the first evidence that enhanced MuSK expression can ameliorate the loss of postsynaptic AChRs in a mouse model of MuSK-MG.