PML as a neuroprotective guardian: Leveraging nuclear protein quality control to mitigate neurotoxicity of an ALS ‐associated NEK1 variant

Insoluble protein aggregates are a hallmark of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). The ubiquitin–proteasome system (UPS) serves as a neuroprotective quality control mechanism that clears aggregates. PML nuclear bodies (NBs) were proposed to serve as hubs for SUMO‐primed ubiquitylation and degradation of misfolded proteins. Georgiadou et al. provide evidence that an ALS‐linked NEK1 truncation mutant is recruited to PML NBs, where it likely undergoes SUMOylation and ubiquitylation. In mice, PML loss exacerbates ALS‐like symptoms, while induced PML expression delays disease onset. These findings establish PML as a key regulator of proteostasis and highlight PML induction as a potential therapeutic strategy for ALS and related proteinopathies.