Özet:
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with dismal prognosis, characterized by motor neuron loss in the patients. More than 30 genes have been reported to be involved in ALS pathogenesis. Most recently, re searchers identified novel mutations on NEK1, a kinase that functions in several pro cesses including cell cycle control and early DNA damage response. However, how mutant NEK1 drives ALS pathogenesis is hitherto unknown. Here we reveal that a NEK1 variant commonly found in ALS patients, truncated NEK1 (tNEK1), displays altered subcellular localization and is trapped in the nucleus due to the loss of two nuclear export signals in the mutant form. We show that tNEK1 displays massive loss of solubility, forming dramatic intracellular aggregates, a phenomenon commonly seen in most ALS cases. Nuclear tNEK1 is recruited in Promyelocytic Leukemia (PML) Nuclear Bodies (NBs) which act as catalytic chambers that promote Ubiquitin-like modifications and initiate protein degradation; consistent with this, we found that tNEK1 undergoes massive modification by Small Ubiquitin-Like Modifier (SUMO). Drugs that enhance PML NB biogenesis and function, such as interferon alpha (IFN), promote tNEK1 recruitment in PML NB, its post-translational modifications and sub sequent destruction by the proteasome, likely before it gets a chance to aggregate. In conclusion, in our study we shed light on how a NEK1 mutant might drive ALS pathogenesis, and identify IFN as a potential treatment for tNEK1-linked ALS cases.
