Loss of Function of the ALS-associated NEK1 Kinase Disrupts Microtubule Homeostasis and Nuclear Import

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 Aug 16

PMID 37585529

Authors

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

Affiliations

Soon will be listed here.

Abstract

Loss-of-function variants in NIMA-related kinase 1 (NEK1) constitute a major genetic cause of amyotrophic lateral sclerosis (ALS), accounting for 2 to 3% of all cases. However, how mutations cause motor neuron (MN) dysfunction is unknown. Using mass spectrometry analyses for NEK1 interactors and NEK1-dependent expression changes, we find functional enrichment for proteins involved in the microtubule cytoskeleton and nucleocytoplasmic transport. We show that α-tubulin and importin-β1, two key proteins involved in these processes, are phosphorylated by NEK1 in vitro. NEK1 is essential for motor control and survival in models in vivo, while using several induced pluripotent stem cell (iPSC)-MN models, including NEK1 knockdown, kinase inhibition, and a patient mutation, we find evidence for disruptions in microtubule homeostasis and nuclear import. Notably, stabilizing microtubules with two distinct classes of drugs restored NEK1-dependent deficits in both pathways. The capacity of NEK1 to modulate these processes that are critically involved in ALS pathophysiology renders this kinase a formidable therapeutic candidate.

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