Peripheral and central neuronal circuit defects in ALS genetic models

The loss of connection between muscles and motor neurons at neuromuscular junctions occurs early and throughout the progression of ALS. Defects arising in synapses, the spaces between neurons where electrical and chemical signals pass from one neuron to another, are not well understood.

In previous work, Dr. Armstrong has successfully created zebrafish models of ALS and conducted lab experiments to study the nature of defects in neuromuscular junctions and synapses in the spinal cord. Zebrafish are uniquely suited to these studies because they are transparent, allowing researchers to see biological responses easily. However, with older technology, the zebrafish ALS models may not represent the human disease in the right way.

With this grant, Dr. Armstrong will use a powerful new gene editing tool called CRISPR-Cas9 to genetically modify zebrafish to express the TDP-43 and FUS forms of ALS. He hopes that by more accurately representing the genetic situation in human ALS he will have a more in-depth opportunity to examine the cellular defects that arise in synapses within the spinal cord and in neuromuscular junctions that connect the brain and spinal cord to muscles. New insights about the circuitry between muscles and motor neurons may provide a more complete understanding of how ALS arises and one day, could lead to new treatment approaches. Further, if CRISPR-Cas9 proves to be a successful gene-editing tool to create better zebrafish models of ALS, the learning will pave the way for using it to create better models of ALS in other animals in future research.