The loss of pml accelarates als driven by mutant nek1 aggregation, but pharmacological induction of pml-mediated degradation offers a potential clinical reversal

Mono-allelic loss-of-function mutations in the NEK1 gene are linked to the development of Amyotrophic Lateral Sclerosis (ALS), with varying degrees of penetrance, potentially due to haploinsufficiency. In a mouse model of ALS carrying the Arg812Ter mutation in NEK1, the resulting truncated protein (NEK1t) tends to aggregate, especially in alpha motoneurons (αMNs), leading to the onset of ALS-like symptoms when expressed biallelically. An important genetic modifier in this process is Promyelocytic Leukemia (Pml), as its absence can trigger ALS-like features even in heterozygous mice with a functional wild-type Nek1 allele, mimicking human disease phenotypes. Pml plays a protective role by promoting the SUMO-mediated degradation of NEK1t aggregates, thereby preventing disease progression. Activation of Pml, through treatments with IFNα or poly (I:C), effectively clears NEK1t aggregates in αMNs and significantly reduces ALS symptoms in Nek1t/t mice, extending their lifespan by up to six months. This research emphasizes the critical role of NEK1t aggregation in ALS pathogenesis which suggests that boosting Pml activity through IFNα or poly (I:C) could serve as a potential therapeutic approach to mitigate the effects of toxic misfolded proteins in ALS.