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

• Type of Material: Article
• Authors: Hayley Robinson, Cleveland Clinic; Sk Imran Ali, Cleveland Clinic; Martha Elena Diaz-Hernandez, Emory University; Rodrigo Lopez-Gonzalez, Cleveland Clinic
• Language: English
• Date: 2022-06-13
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Robinson, Ali, Diaz-Hernandez and Lopez-Gonzalez.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fcell.2022.874323
• Title of Journal or Parent Work: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
• Volume: 10
• Start Page: 874323
• End Page: 874323
• Keywords: NEURODEGENERATION; LENGTH; EXPRESSION; MITOCHONDRIAL-FUNCTION; HEXANUCLEOTIDE REPEAT; OXIDATIVE STRESS; Cell Biology; C9orf72; ALZHEIMERS-DISEASE; Science & Technology; Frontotemporal dementia; Life Sciences & Biomedicine; TRF2; Amyotrophic lateral sclerosis; APOE-EPSILON-4; motor neuron differentiation; Developmental Biology; telomeres; induced pluripotent stem cells; DIFFERENTIATION
• Research Categories: Biology, Neuroscience; Health Sciences, Medicine and Surgery

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.