Structural and Pathogenic Mechanisms Centered on Muscle-Specific Tyrosine Kinase in Autoimmune Neuromuscular Junction Disorders
Pages 207-213 (7)
Myasthenia gravis (MG), an autoimmune neuromuscular junction disorder characterized by fatigable weakness
of voluntary muscles including ocular, facial, oropharyngeal, limb and respiratory muscles with a prevalence of about
150-200 per million, is a disease of the postsynaptic neuromuscular junction where acetylcholine receptors (AChRs) are
targeted by autoantibodies in 80-85% of MG patients. We face unresolved issues in the efforts to clarify the pathogenesis
of remaining MG patients (seronegative MG). In this regard, we have paied attention to the findings that part of
seronegative MG patients have antibodies against other postsynaptic proteins: the muscle-specific tyrosine kinase (MuSK)
which is activated by Dok-7 (muscle adaptor protein) and plays a key role in AChR clustering at the end-plate membrane,
and the low-density lipoprotein receptor-related protein 4 (Lrp4) which is the agrin receptor and mediates the neural signal
to MuSK. To search a clue to further understanding of the immunopathological mechanisms underlying postsynaptic
junction disorders, we need to understand a complex architecture formed by diversity of elements through signals
orchestrated by sophisticated interactions in the synapse. The present review focuses on the signaling downstream from
MuSK which is originated from the activation by agrin/Lrp4 signaling (via MuSK immunoglobulin-like domains 1 and 2)
and by Wnt signaling (via MuSK cysteine-rich domain (CRD)), and also focuses on the synaptic stability by extracellular
matrix proteins (such as collagen Q, perlecan and biglycan) and their receptors (via dystroglycans). Also, the review may
shed light on possible mechanisms (including Wnt/MuSK CRD, Lrp4 and laminin-network) to modify the presynaptic
function in autoimmune postsynaptic disorders.
Acetylcholine receptor, Agrin, laminin-network, Lrp4, MuSK, myasthenia gravis, neuromuscular junction, Wnts.
Neurological Center, Kanazawa-Nishi Hospital, 6-15-41, Ekinishi-Honmachi, Kanazawa City, Ishikawa-ken, 920-0025, Japan.