Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related Repeat Expansion Carriers.

The GGGGCC (G4C2) repeat expansion in is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dysregulated DNA damage response and the generation of reactive oxygen species (ROS) have been postulated as major drivers of toxicity in pathogenesis. Telomeres are tandem-repeated nucleotide sequences that are located at the end of chromosomes and protect them from degradation. Interestingly, it has been established that telomeres are sensitive to ROS. Here, we analyzed telomere length in neurons and neural progenitor cells from several induced pluripotent stem cell (iPSC) lines from control subjects and repeat expansion carriers. We found an age-dependent decrease in telomere length in two-month-old iPSC-derived motor neurons from carriers as compared to control subjects and a dysregulation in the protein levels of shelterin complex members TRF2 and POT1.