Axonal degeneration as a therapeutic target for ALS

Motor neurons are the living wires within our bodies that carry electrical signals from our brain to our muscles. What makes motor neurons unique compared to other cell types is their shape. Motor neurons have a long cable called the axon that carries electrical impulses through the cell to either the next motor neuron in the chain or a muscle, causing it to contract.

The axon is a dynamic structure, changing in response to external stimuli leading to growth (regeneration), branching, or retraction (degeneration). Damage to the axon has been observed in a variety of neurodegenerative diseases, including ALS. Some suggest that axonal degeneration may be one of the first steps in the onset of ALS and previous studies have shown that damage to the axon can cause symptoms even when the cell body of the motor neuron is intact.

Dr. Parker and his team hypothesized that stimulation of specific genetic pathways known to promote axon regeneration may help to delay the onset or slow the progression of ALS. In Dr. Parker’s lab, they use small worms, called C. elegans, to model ALS. These worms are only a millimetre long, but since they have short lifespans and share 60 per cent of their genetic makeup with humans, they are ideal animals to use in research.

In this study, Dr. Parker and team will build upon previous foundational work within the lab. First the team will identify specific genetic pathways shown to supress axon degeneration. Then they will test various small molecule inhibitors of proteins linked to these pathways to assess their potential as future treatment options for ALS. Finally, in collaboration with Dr. Armstrong, they will validate these findings in zebrafish and human iPSC ALS models. The results from this study will help to reveal new targets for therapeutic development with the ultimate goal of moving promising candidates into clinical testing.