We identified a mechanism organizing mammalian NMJs where muscle-derived synapse organizer laminin β2 anchors PQ-type voltage-gated calcium channels (VGCCs) at the presynaptic membrane. The anchored VGCCs function as a scaffolding protein for the active zone-specific proteins, including Bassoon, to organize the synaptic vesicle release site.

STED super-resolution microscopy analysis of NMJs in wild-type mice revealed synaptic protein distribution patterns that supported our molecular mechanism of active zone organization. Furthermore, we found that levels of active zone proteins, Bassoon, Piccolo, and PQ-type VGCC, decreased in innervated NMJs of SOD1G93A mice compared to age- and sex-matched wild-type mice.

We also found that the protein level of synapse organizer laminin β2 decreased in NMJs of SOD1G93A mice, and transgenic expression of laminin β2 in skeletal muscles of SOD1G93A mice ameliorated NMJ denervation.

As a therapeutic source of laminin β2, we identified that stimulating human umbilical cord-Wharton’s jelly derived mesenchymal stem cells (hMSCs) in media supplemented with growth factors can increase laminin β2 and neurotrophic factor secretion.

We confirmed that unilateral injection of hMSCs increased NMJ innervation rates and average myofiber cross-sectional area in MSC-injected muscles compared to non-injected contralateral muscles. Importantly, hMSCs obtained from the two donors improved the neuromuscular function of injected SOD1G93A mice and prolonged the lifespan of these mice compared to the vehicle-injected SOD1G93A mice.

This study suggests that the loss of synapse organizer laminin β2 causes denervation of ALS NMJs, and a treatment to supplement laminin β2 may reduce NMJ denervation and improve the quality of life of ALS patients.

 

About the speaker

Dr Hiroshi Nishimune, Professor of Anatomy and Cell Biology at University of Kansas School of Medicine USA, studies the development, maintenance, aging, and pathology of neuromuscular junctions (NMJs). Dr Nishimune obtained PhD at Osaka University, Japan and trained as a postdoctoral fellow in Dr Christopher Henderson’s lab at INSERM U382, France studying neurotrophic factors, and in Joshua Sanes’ lab at Harvard University, USA studying NMJ development.

Dr Nishimune elucidated the molecular mechanism that organizes active zones, synaptic vesicle release sites, at presynaptic terminals of mammalian NMJs. Recently, he investigates degeneration of NMJs in rodent models of ALS and ageing.

About Research Seminar Series

The School of Biomedical Sciences Seminar Series presents seminars by international and national researchers as well as local researchers and postdocs.

Unless otherwise indicated, seminars are held in the QBI Auditorium, Level 7 on Mondays from 1.00-2.00pm.

Venue

Room: 
63-348