Targeting neuromuscular synapses as a new therapeutic approach for muscle weakness and atrophy

Dear All,

Cell Signal Unit (Yamamoto Unit) would like to inform you of a seminar by Dr. Yuji Yamanashi from The Institute of Medical Science, The University of Tokyo.

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Date: Tuesday, August 7, 2018

Time: 13:30-14:30

Venue: C016, Level C, Lab 1

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Speaker:

Dr. Yuji Yamanashi from The Institute of Medical Science, The University of Tokyo

Title:
Targeting neuromuscular synapses as a new therapeutic approach for muscle weakness and atrophy

Abstract:

The neuromuscular junction (NMJ) is a synapse between a motor neuron and skeletal muscle. Defective neuromuscular transmission gives rise to the fatigable muscle weakness known as myasthenia. The formation of the NMJ is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, which can activate MuSK via the coreceptor Lrp4. However, we demonstrated that the muscle protein Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the kinase, and that neural agrin requires Dok-7 in order to activate MuSK at least in cultured myotubes. Consistently, we demonstrated that Dok-7 is essential for neuromuscular synaptogenesis, and mutations in DOK7 underlie a limb-girdle type of congenital myasthenic syndrome, DOK7 myasthenia, which is associated with NMJ defects. Accumulating evidence shows that many neuromuscular disorders, such as myasthenia, muscular dystrophy, motor neurodegenerative diseases (including HMSN-P-related ones), and age-related muscle weakness, are associated with NMJ defects at least in animal models.

Previously, we generated Dok-7 transgenic mice, which overexpress Dok-7 in skeletal muscle, and found that they have large NMJs without any obvious defects in motor performance. Therefore, we set out to develop a possible therapeutic approach for NMJ defects, namely, enlarging/protecting NMJs. We first generated the adeno-associated virus vector AAV-D7, which expresses DOK7, and demonstrated that postnatal administration of AAV-D7 enlarged NMJs in mice. Thus we generated a mouse model of DOK7 myasthenia and demonstrated that therapeutic administration of AAV-D7 enlarged NMJs and enhanced their motor activities and life span. Moreover, this new treatment is also beneficial to mouse models of other neuromuscular disorders including muscular dystrophy and amyotrophic lateral sclerosis. Therefore, we propose that elevated Dok-7 expression, or any equivalent method that stably and safely enlarges NMJs, has potential as a therapy for a range of neuromuscular disorders with NMJ defects.

Host:
Prof. Tadashi Yamamoto

We hope to see many of you at the seminar.

Best regards,

Yuki Nakagawa

Research Unit Administrator

Cell Signal Unit