Pml loss worsens NEK1-linked ALS and Pml induction drives NEK1 degradation, precluding disease onset - PubMed
3 days ago
- #NEK1
- #ALS
- #PML
- 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).
- Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1t puncta in αMNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months.
- The study highlights the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy.
- Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo yields dramatic clinical improvement.
- These observations validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.