Stem Cell Modeling of Neuroferritinopathy Reveals Iron as a Determinant of Senescence and Ferroptosis during Neuronal Aging

Publication date: Available online 3 October 2019Source: Stem Cell ReportsAuthor(s): Anna Cozzi, Daniel I. Orellana, Paolo Santambrogio, Alicia Rubio, Cinzia Cancellieri, Serena Giannelli, Maddalena Ripamonti, Stefano Taverna, Giulia Di Lullo, Ermanna Rovida, Maurizio Ferrari, Gian Luca Forni, Chiara Fiorillo, Vania Broccoli, Sonia LeviSummaryNeuroferritinopathy (NF) is a movement disorder caused by alterations in the L-ferritin gene that generate cytosolic free iron. NF is a unique pathophysiological model for determining the direct consequences of cell iron dysregulation. We established lines of induced pluripotent stem cells from fibroblasts from two NF patients and one isogenic control obtained by CRISPR/Cas9 technology. NF fibroblasts, neural progenitors, and neurons exhibited the presence of increased cytosolic iron, which was also detectable as: ferritin aggregates, alterations in the iron parameters, oxidative damage, and the onset of a senescence phenotype, particularly severe in the neurons. In this spontaneous senescence model, NF cells had impaired survival and died by ferroptosis. Thus, non-ferritin-bound iron is sufficient per se to cause both cell senescence and ferroptotic cell death in human fibroblasts and neurons. These results provide strong evidence supporting the primary role of iron in neuronal aging and degeneration.Graphical Abstract

Source: Stem Cell Reports - October 4, 2019 Category: Stem Cells Source Type: research