Scientists have discovered for the first time how a mutated gene leads to amyotrophic lateral sclerosis (ALS) -- a progressive neurodegenerative that affects nerve cells in the brain and spinal cord.

It has been known that mutations in the gene NEK1 have been linked to as much as 2 per cent of all ALS cases, making it one of the top-known causes of the disease. But it wasn’t known how the mutated gene disrupts the function of the motor neuron and causes it to degenerate and die.

The team from Northwestern University found that the mutation causes the structures supporting the axon in the neuron to become less stable and susceptible to collapsing. (The axon is the thinner-than-a-human-hair cable leading from the cell that sends electrical messages to other neurons.)

They also discovered that the mutation disrupts the ability of the neuron to import cargo in the form of RNA or proteins into its nucleus, a process called nuclear import.

Without the import of RNA -- which carries instructions from the DNA -- and critical proteins, the operational role of the nucleus for the cell’s function is disrupted. They reported their findings in the journal Science Advances.

"By illuminating these two pathways, we're suggesting these are great therapeutic targets for the disease," said lead author Evangelos Kiskinis, Assistant Professor of Neurology and Neuroscience at Northwestern University Feinberg School of Medicine.

“This discovery is important because a breakthrough in ALS research in the last few years was discovering that nuclear import is disrupted in other forms of genetic ALS,” Kiskinis said.

“We are linking this new cause of ALS to other genetic causes in which the same process is disrupted.”

ALS is a devastating neurodegenerative disease in which the upper and lower motor neurons in the brain and spinal cord are dysfunctional and die. It results in the loss of voluntary muscle movement, which leads to paralysis and eventual death.

The structural components of the nerve’s axon, which are destabilised in ALS, are microtubules. Anti-cancer drugs such as paclitaxel, which target and stop the dividing of cancer cells, are known to help stabilise the microtubules.

So, the team tested these anti-cancer drugs in ALS models of human neurons (made from ALS patients’ stem cells). The drugs stabilised the microtubules in vitro and restored the ability of nerve cells with the ALS mutation to function.

Kiskinis said it would be exceptionally challenging to use such anti-cancer drugs to treat ALS patients as they would likely have severe side effects and a very narrow dose range as over-stabilising microtubules can be toxic to neurons. However, the findings serve as proof of principle.

“This suggests that stabilising microtubules is a rational therapeutic approach in ALS,” Kiskinis said.