Mouse study of MuSK MG reveals cause - opens door to possible therapies

If you're feeling strangely tired and droopy-eyed, especially toward the end of the day or if you're occasionally seeing double and slurring your speech, there's a slight chance – 1 in 5,000 for Americans – that you have myasthenia gravis (MG). The chances are even slimmer – less than 1 in 50,000 – that you have a rare form of MG that doesn't respond well to available treatments (MuSK). There's no cure for MG, only treatments that alleviate the symptoms. But hope may be on the horizon for those who have
the rare form. Recently, a Japanese research team led by Drs. Kazuhiro Shigemoto and Shuuichi Mori, both from the Tokyo Metropolitan Institute of Gerontology, characterized the A/WySnJ mouse (000647) as a model of the rare form of MG and demonstrated that an aminopyridine drug can mitigate its symptoms (Mori et al. 2012a, 2012b).

Myasthenia gravis
MG is a little-understood, chronic, autoimmune disease characterized by fluctuating weakness of the voluntary muscles. Indeed, the words myasthenia gravis are derived from the Greek and Latin words that mean "grave muscular weakness." In addition to the drooping eyelids, blurred or double vision, and slurred speech mentioned above, symptoms include difficulty chewing and swallowing, weakness in the arms and legs, chronic muscle fatigue, and difficulty breathing. MG affects people of every age, sex, and race. It is presumably not inherited and not contagious.

Molecularly, MG is caused by poor nerve-to-muscle communication at neuromuscular junctions (NMJs). For nerve impulses to make muscles move, a process called synapse must occur: a neurotransmitter, usually acetylcholine (ACh), must be released from the motor neurons (pre synapse) and bind to ACh receptors (AChRs) on the muscle cells (post synapse). MG is the most common disease of neuromuscular synapses.

The majority of people with MG produce antibodies that destroy their own AChRs through a complement pathway. This form of MG is called AChR-MG. AchR-MG symptoms can be alleviated with acetylcholinesterase (AChE) inhibitors, which inhibit the degradation of ACh at post-synaptic NMJs.

A minority of people with MG don't produce anti-AChR antibodies. Instead, they produce antibodies against muscle-specific kinase (MuSK), a protein essential to the formation, maintenance, and function of NMJs. These antibodies destroy MuSK independently of complement. This form of MG is called MuSK-MG. AChE inhibitors are generally ineffective against and may even aggravate MuSK-MG.

Continue >>> The A/WySnJ mouse, a model of MuSK-MG