Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset

Germinal mono-allelic loss-of-function mutations of NEK1 drive Amyotrophic Lateral Sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1t) is aggregation-prone, particularly in alpha-motoneurons (αMNs), and drives canonical ALS symptoms when bi-allelically expressed (Nek1t/t). Promyelocytic leukemia (Pml) ablation allows for ALS symptoms to occur even in heterozygote Nek1wt/t animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1t proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1t aggregates in αMNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of NEK1 aggregates in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that not only promotes Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo, but also facilitates the clearance of protein aggregates, yielding dramatic clinical improvement. These observations validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein aggregation.