DNA repair pathways are altered in neural cell models of frataxin deficiency

• Published in: Molecular and cellular neuroscience Vol. 111; p. 103587
• Main Authors: Moreno-Lorite, Jara, Pérez-Luz, Sara, Katsu-Jiménez, Yurika, Oberdoerfer, Daniel, Díaz-Nido, Javier
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2021
• Subjects: Animals; Apoptosis; Cell Line, Tumor; Cells, Cultured; Cellular models; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; Frataxin; Friedreich Ataxia - genetics; Friedreich Ataxia - metabolism; Friedreich's ataxia; Humans; Iron-Binding Proteins - genetics; Iron-Binding Proteins - metabolism; Mice; Mice, Inbred C57BL; Neurodegeneration; Neurons - metabolism; Oxidative Stress; Tumor Suppressor Protein p53 - metabolism; Friedreich's ataxia; Frataxin; Neurodegeneration; DNA damage; Cellular models
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2020.103587

Friedreich's ataxia (FRDA) is a hereditary and predominantly neurodegenerative disease caused by a deficiency of the protein frataxin (FXN). As part of the overall efforts to understand the molecular basis of neurodegeneration in FRDA, a new human neural cell line with doxycycline-induced FXN knockdown was established. This cell line, hereafter referred to as iFKD-SY, is derived from the human neuroblastoma SH-SY5Y and retains the ability to differentiate into mature neuron-like cells. In both proliferating and differentiated iFKD-SY cells, the induction of FXN deficiency is accompanied by increases in oxidative stress and DNA damage, reduced aconitase enzyme activity, higher levels of p53 and p21, activation of caspase-3, and subsequent apoptosis. More interestingly, FXN-deficient iFKD-SY cells exhibit an important transcriptional deregulation in many of the genes implicated in DNA repair pathways. The levels of some crucial proteins involved in DNA repair appear notably diminished. Furthermore, similar changes are found in two additional neural cell models of FXN deficit: primary cultures of FXN-deficient mouse neurons and human olfactory mucosa stem cells obtained from biopsies of FRDA patients. These results suggest that the deficiency of FXN leads to a down-regulation of DNA repair pathways that synergizes with oxidative stress to provoke DNA damage, which may be involved in the pathogenesis of FRDA. Thus, a failure in DNA repair may be considered a shared common molecular mechanism contributing to neurodegeneration in a number of hereditary ataxias including FRDA. •iFKD-SY frataxin-deficient cells present a decrease in aconitase activity restored after doxycycline withdrawal•iFKD-SY frataxin-deficient cells showed increased oxidative stress restored after doxycycline withdrawal•Frataxin knockdown triggers cell cycle arrest and apoptosis only under levels of frataxin in the range of FRDA patients•iFKD-SY cells can differentiate into neuron-like cells, although frataxin deficiency elicits a massive apoptotic death•Frataxin deficiency is associated with altered expression of genes involved in DNA repair pathways