MND and Me Foundation Research Grant – Update August 2018 – MND and Me Foundation

MND and Me Foundation Research Grant – Update August 2018

Researchers: Associate Professor Peter G. Noakes, Dr Shyuan T. Ngo, Associate Professor William D. Phillips, & the MND QLD Research Collective.


Muscle weakness is an early symptom of MND in patients.  Research from patients with MND, and from mice created to develop MND symptoms, show that this occurs due to the loss of motor nerve muscle connections.  Motor nerves, located in the spinal cord, connect with muscles and cause the muscle to contract, this is called a neuromuscular connection.  Our research has been investigating how neuromuscular connections are lost in MND.  So far, our studies in patients with MND, and mice created to study MND, have shown that there is a loss of adhesion between motor nerves and muscle cells, along with a loss of molecules needed for muscles to contract.


The loss of adhesion is due to the decrease in the amount of a group of molecules called laminins which are located between the motor nerve ending and the muscle cell.  Laminins are responsible for holding the motor nerve ending on to the muscle fibre.  We have observed this loss in the adhesion laminins -a4, -a5 and -b2 at human neuromuscular connections in muscle from several early diagnosed patients with MND, and in mice before they develop symptoms of MND.


The drop in these adhesive laminins could explain some of the early features that we, and others, have seen at neuromuscular connections in MND patients; such as withdrawal of the motor nerve from muscle, and the invasion of another cell, the Schwann cell, that may lift the motor nerve ending off the muscle.


Acetylcholine receptors are proteins in the muscle membrane which respond to chemicals from the motor nerve ending and cause the muscle to contract.  MuSK is another protein that is located next to these receptors, which, when activated, causes these receptors to gather in large amounts in the muscle surface below where the motor nerve attaches.  Agrin, a molecule released by the motor nerve, activates MuSK to cause this process to happen.  We have been able to generate muscle cells from patients with MND and healthy control donors, grow them in a dish, and assess their ability to cluster acetylcholine receptors on the surface of muscle cells in response to Agrin.  So far, we have seen that muscles from patients with MND do not respond to Agrin to form large clusters of Acetylcholine receptors.  This could be due to a drop in the level of MuSK in the muscle cell.


We believe that improving the levels of the laminins -a4, -a5, and -b2, along with MuSK, will help stabilise the connection between motor nerves and muscle, and hence slow the rate of muscle weakness and paralysis, thereby providing a better quality of life for patients.