eNews June 08, 2012

Mouse models rare form of myasthenia gravis

One in 5,000 Americans has myasthenia gravis (MG). There's an even slimmer chance – less than one in 50,000 – that you have a rare form of MG that doesn't respond well to available treatments. There's no cure for MG, only treatments that alleviate the symptoms. Hope may be on the horizon for people 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 MG’s 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 drooping eyelids, blurred or double vision, and slurred speech, 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.

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

The A/WySnJ mouse is widely used in cancer and immunology research. The Shigemoto/Mori team contributed significantly to characterizing it as a MuSK-MG model. They found that, when immunized with MuSK protein, this mouse develops a human-like MuSK-MG disease. It produces anti-MuSK antibodies and loses weight. Its muscles weaken, its synapses degrade, and its electromyographic pattern is similar to that of people with MuSK-MG. Its NMJs are structurally and functionally altered. Like people with MuSK-MG, it doesn't produce anti-AChR antibodies, and its disease is not complement mediated. In fact, the A/WySnJ mouse is deficient in hemolytic complement C5. Like people with MuSK-MG, the MuSK-immunized A/WySnJ mouse is hypersensitive to ACh and AChE inhibitors, and it has low levels of ACh, AChE, and AChE-anchoring protein collagen Q at postsynaptic membranes. Its NMJ nerve terminals release abnormally low levels of ACh. The same appears to be true in humans with MuSK-MG. Whereas AChR-MG is due to a post-synaptic defect (defective AChRs), MuSK-MG is due to both post- and a pre-synaptic defects (defective AChRs and ACh release). The low levels of ACh, AChE, and AChE-anchoring protein collagen Q likely explain why AChE inhibitors exacerbate human MuSK-MG.

Other mouse models of MuSK-MG

The Shigemoto/Mori team found that other complement-deficient mice – such as C5-deficient A/J (000646), DBA/2J (000671), FVB/NJ (001800) and C3-deficient B6;129S4-C3tm1Crr/J (003641) mice – develop MuSK-induced MG. In contrast, complement-sufficient mice – such as BALB/cJ (000651) and C57BL/6J (000664) – are less susceptible, indicating that complement deficiency mediates a more severe MuSK-MG disease phenotype.

3.4-DAP improves muscle function in A/WySnJ mice

As mentioned earlier, though AChE inhibitors can improve synapse in people with AChR-MG, they are generally ineffective and may even aggravate MuSK-MG. This may be because people with MuSK-MG are hypersensitive to ACh. To find a more appropriate therapy for MuSK-MG, the Shigemoto/Mori team explored the possibility that 3,4-diaminopyridine (3,4-DAP), a powerful inducer of neurotransmitter release from NMJ nerve terminals, could improve synapse in MuSK-immunized A/WySnJ mice. They found that a single injection of 3,4-DAP significantly increases muscle strength and function in these mice. They attribute 3,4-DAP's efficacy to its ability to increase ACh release from the NMJ nerve terminals. They suggest that, in combination with a low dose of AChE inhibitors, it might do the same to alleviate the symptoms of MuSK-MG in people.

In summary, the Shigemoto/Mori team characterized a new mouse model of MuSK-MG, a rare form of myasthenia gravis, clarified the pathogenesis of human MuSK-MG, and paved the way for the development of new therapies for the disease.