ALS driven by mutant NEK1 aggregation is accelerated by Pml loss, but clinically reversed through pharmacologic induction of Pml-mediated degradation

ABSTRACT

Germinal mono-allelic loss-of-function mutations of NEK1 drive Amyotrophic Lateral Sclerosis (ALS) at variable penetrance, potentially through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated NEK1 (NEK1^t) is aggregation-prone, notably in alpha-motoneurons (αMNs), and drives multiple ALS-like symptoms when bi-allelically expressed. Promyelocytic leukemia (Pml) is a key genetic interactor, since its loss allows for ALS symptoms to occur even in Nek1^wt/t animals, mimicking the human situation. Pml precludes disease onset by promoting SUMO-facilitated degradation of NEK1^t proteins. Pml upregulation by interferon alpha or poly(I:C) eliminates NEK1^t aggregates in αMNs of Nek1^t/t animals, dramatically improving ALS-associated symptoms and extending survival by 6 months. Our study highlights the role of NEK1 aggregates in ALS pathogenesis and identifies interferon or poly(I:C) as a promising candidate therapy acting through Pml-triggered degradation of toxic misfolded proteins.