Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related C9ORF72 Repeat Expansion Carriers

Hayley Robinson; Sk Imran Ali; Martha Elena Diaz-Hernandez; Rodrigo Lopez-Gonzalez

doi:10.3389/fcell.2022.874323

Telomere Attrition in Induced Pluripotent Stem Cell-Derived Neurons From ALS/FTD-Related C9ORF72 Repeat Expansion Carriers

Front Cell Dev Biol. 2022 Jun 13:10:874323. doi: 10.3389/fcell.2022.874323. eCollection 2022.

Authors

Hayley Robinson¹, Sk Imran Ali¹, Martha Elena Diaz-Hernandez^{2

3}, Rodrigo Lopez-Gonzalez¹

Affiliations

¹ Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
² Department of Orthopaedics, Emory University, Atlanta, GA, United States.
³ Atlanta VA Medical Center, Decatur, GA, United States.

Abstract

The 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 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 C9ORF72 repeat expansion carriers. We found an age-dependent decrease in telomere length in two-month-old iPSC-derived motor neurons from C9ORF72 carriers as compared to control subjects and a dysregulation in the protein levels of shelterin complex members TRF2 and POT1.

Keywords: Amyotrophic lateral sclerosis, Frontotemporal dementia; C9orf72; induced pluripotent stem cells; motor neuron differentiation; telomeres.