Functionele validatie van TET2 als genetische modificator in Amyotrofische laterale sclerose

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable disease, characterized by the selective and progressive degeneration of upper and lower motor neurons in the motor cortex, brain stem and spinal cord. Loss of motor neurons results in muscle weakness, paralysis and eventual death due to respiratory failure, typically within 2-5 years after diagnosis. The clinical presentation can strikingly differ between patients, with e.g. great variability in age of onset and survival. This phenotypic variability is not only present in sporadic ALS cases with a largely unknown etiology, but also in familial cases caused by identical inherited mutations. This indicates that genetic and/or environmental factors that can modify the clinical phenotype are present. Therefore, in this study, we aimed to identify and functionally validate genes carrying rare genetic variants that influence the age of onset in ALS. We showed that rare loss-of-function mutations in TET2 and ASXL1 are associated with a delayed age at onset in ALS. In addition, we established a timeline of ALS-related phenotypes in TARDBP-mutant spinal motor neurons (sMNs). Lastly, functional validation of TET2 as candidate modifier provided evidence that TET2 downregulation has a neuroprotective effect in patient-derived sMNs and highlighted the potential of TET2 as target for therapeutic interventions.