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 (Nek1 t ) is aggregation‐prone, particularly in alpha‐motoneurons (αMNs), and drives canonical ALS symptoms when bi‐allelically expressed ( Nek1 t/t ) . Promyelocytic leukemia ( Pml ) ablation allows for ALS symptoms to occur even in heterozygote Nek1 wt/t animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO‐facilitated degradation of Nek1 t proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1 t puncta in αMNs, dramatically reducing ALS‐associated symptoms and extending survival by 5 months. Our studies highlight the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that promotes Pml‐ triggered SUMOylation/degradation of toxic misfolded proteins in vivo , yielding dramatic clinical improvement. These observations provide strong proof‐of‐concept support to validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.