A Potential New Target for ALS Therapies

The Context: Mutations in a gene called NEK1 are known to cause ALS in a subset of patients, but how exactly these mutations affect motor neurons (the cells implicated in ALS) to drive the disease is not well understood.

The Study: A mutated in NEK1 gene affects key components of motor neurons including their shape and ability to deliver cellular cargo to the nucleus (the cell’s ‘command center’), finds a new study in Science Advances by NYSCF – Robertson Stem Cell Investigator (and NYSCF – Druckenmiller Fellow Alumnus) Evangelos Kiskinis, PhD, of Northwestern University.

The Importance: This study illuminates the role of NEK1 in ALS and suggests it could serve as a future target for therapies.

ALS is a difficult disease to treat, as symptoms and progression can present very differently across patients. Having more defined targets for therapeutics will help open the door for precision medicine, and this work helps identify one such target in the gene NEK1.

“ALS-causing mutations in the NEK1 gene were identified in 2015, but how this gene causes disease has remained relatively unexplored since then,” said Elizabeth McKenna, PhD, a co-first author in the study, in an article from Northwestern Medicine. 

Investigating NEK1

First, the team used stem cells to create motor neurons, and decreased the activity of NEK1, finding that this impacted proteins involved in two important cellular processes: the ability to maintain the stability of the fibers that help neurons communicate (mediated by cell scaffolding structures called ‘microtubules’) and the ability to transport important cell cargo in and out of the nucleus.

“We identified several proteins implicated in NEK1 function, which are also known to function in the microtubule cytoskeleton and the nucleocytoplasmic transport pathways, leading us to investigate those pathways more closely,” noted Dr. McKenna.

Inside ALS-Affected Cells

Then, the team made motor neurons from the stem cells of ALS patients with NEK1 mutations, and found the same deficiencies in microtubule formation and cellular transport.

Interestingly, an anti-cancer drug called paclitaxel was able to help stabilize microtubules and restore normal cellular transport.

All of this points to NEK1 as a potential target for future ALS therapies, and the team will continue to study the role of this gene in the disease.

“For the first time, we have characterized the impact of NEK1 loss of function, enzymatic inhibition as well as ALS associated in human motor neurons derived from stem cells,” said Dr. Kiskinis. “We found that NEK1 compromises nuclear import and microtubule homeostasis, two pathways previously implicated in other forms of ALS. The capacity of NEK1 to modulate these neuronal processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate.”

Journal Article:

Loss of function of the ALS-associated NEK1 kinase disrupts microtubule homeostasis and nuclear import
Jacob R Mann, Elizabeth D McKenna, Darilang Mawrie, Vasileios Papakis, Francesco Alessandrini, Eric N Anderson, Ryan Mayers, Hannah E Ball, Evan Kaspi, Katherine Lubinski, Desiree M Baron, Liana Tellez, John E Landers, Udai B Pandey, Evangelos Kiskinis. Science Advances. 2023. DOI: 10.1126/sciadv.adi5548