Telomere attrition in induced pluripotent stem cell derived neurons from ALS/FTD related C9ORF72 repeat expansion carriers

Abstract

AbstractBackgroundThe GGGGCC (G4C2) repeat expansion in C9ORF72 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 C9ORF72 pathogenesis. Telomeres are tandem‐repeated nucleotide sequences that are at the end of chromosomes and protect them from degradation.MethodWe analyzed telomere length in neurons and neural progenitor cells from several induced pluripotent stem cell (iPSC) lines from control subjects and C9ORF72 repeat expansion carriers. In addition, we analyzed RNA levels and protein levels of sheltering complex members.ResultWe found an age‐dependent decrease in telomere length in two‐month‐old iPSC‐derived motor neurons from C9ORF72 carriers as compared to control subjects. We also found a significant decrease in TRF1 and POT1 protein levels in 2 month old motor neurons.ConclusionWe found an ae dependent decrease in telomere length and dysregulation of sheltering complex members in 2‐month old motor neurons from C9ORF72 carriers.