Gene Linked to ALS Disrupts Neuron Structure and Function

A study has described how a gene mutation linked to amyotrophic lateral sclerosis (ALS) disrupts the stability of neurons and “chokes off” their nuclei, impairing their function. The research, published in Science Advances, also describes how anti-cancer drugs improved the stability and function of lab-grown ALS-affected neurons, potentially representing a new therapeutic target.

Uncovering the causes of ALS

ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative condition. It is characterized by the loss of motor neurons, which send impulses from the brain and spinal cord to control voluntary movement. This leads to loss of voluntary muscle control, resulting in paralysis and eventually death.

But despite the devastating prognosis of the disease, we don’t fully understand the causes of ALS. A major point of contention in the field is whether ALS is a single disease or a collection of similar but genetically distinct diseases that fall under a similar clinical umbrella.

In recent years, the gene NIMA-related kinase 1 (NEK1) was linked to ALS, in part thanks to fundraising from the viral phenomenon, the Ice Bucket Challenge. Around 2% of ALS cases are linked to mutations that impair NEK1 function, making it one of its top-known causes given what little we know of the disease. However, it is still unclear exactly how NEK1 mutations lead to impaired motor neuron function – something which researchers from Northwestern University set out to investigate.

Stabilizing neurons as a therapeutic target?

The researchers found that NEK1 mutation causes two problems in the neuron. Firstly, it causes the microtubules – part of the cell’s “skeleton” that supports the structure of the neuron – to become less stable, rendering the neuron prone to collapsing.

Secondly, the mutation disrupts a process called nuclear import. This is the ability of the neuron to import cargo in the form of RNA or proteins into its nucleus; without this cargo, the nucleus’ function is disrupted.

“By illuminating these two pathways, we’re suggesting these are great therapeutic targets for the disease,” said Dr. Evangelos Kiskinis, senior author of the study and assistant professor of neurology and neuroscience at Northwestern University Feinberg School of Medicine.

To investigate in more detail how microtubule instability could impact ALS, the researchers analyzed neurons grown from stem cells with the NEK1 mutation. These were treated with anti-cancer drugs known to stabilize microtubules, such as paclitaxel. The results indicated that this did indeed stabilize the microtubules as well as help increase nuclear imports.

“This suggests that stabilizing microtubules is a rational therapeutic approach in ALS,” Kiskinis said, noting that although treatment with such anti-cancer drugs would be challenging due to side effects, the results serve as a proof-of-principle.

“Our discovery – of the same destructive mechanisms in other genetic forms of ALS – leads us to believe this is the same disease,” Kiskinis said. “This new awareness is critical to developing treatments and for designing optimal clinical trials targeting specific ALS patient populations.”

Next, the team plans to delve into just how NEK1 regulates microtubules and nuclear import in human neurons. They are currently developing approaches that aim to increase NEK1 function in ALS and prevent neuron degeneration.

Reference: Mann JR, McKenna ED, Mawrie D, et al. Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import. Sci. Adv. 2023. doi: 10.1126/sciadv.adi5548

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