Caspase-dependent apoptosis in Riboflavin Transporter Deficiency iPSCs and derived motor neurons

Autor: Marioli C; Department of Science, LIME, University Roma Tre, 00146, Rome, Italy.; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Muzzi M; Department of Science, LIME, University Roma Tre, 00146, Rome, Italy.; Laboratory of Neurodevelopment, Neurogenetics and Neuromolecular Biology, IRCCS Santa Lucia Foundation, 00179, Rome, Italy., Colasuonno F; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy.; Department of Experimental Medicine, University of Rome 'Tor Vergata', 00133, Rome, Italy., Fiorucci C; Department of Science, LIME, University Roma Tre, 00146, Rome, Italy., Cicolani N; Confocal Microscopy Core Facility, Research Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00146, Rome, Italy., Petrini S; Confocal Microscopy Core Facility, Research Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00146, Rome, Italy., Bertini E; Unit of Neuromuscular and Neurodegenerative Disorders, IRCCS Ospedale Pediatrico Bambino Gesù, 00146, Rome, Italy., Tartaglia M; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy., Compagnucci C; Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy. claudia.compagnucci@opbg.net., Moreno S; Department of Science, LIME, University Roma Tre, 00146, Rome, Italy. sandra.moreno@uniroma3.it.; Laboratory of Neurodevelopment, Neurogenetics and Neuromolecular Biology, IRCCS Santa Lucia Foundation, 00179, Rome, Italy. sandra.moreno@uniroma3.it.
Jazyk: angličtina
Zdroj: Cell death discovery [Cell Death Discov] 2024 Jan 26; Vol. 10 (1), pp. 54. Date of Electronic Publication: 2024 Jan 26.
DOI: 10.1038/s41420-024-01812-y
Abstrakt: Riboflavin Transporter Deficiency (RTD) is a rare genetic, childhood-onset disease. This pathology has a relevant neurological involvement, being characterized by motor symptoms, ponto-bulbar paralysis and sensorineural deafness. Such clinical presentation is associated with muscle weakness and motor neuron (MN) degeneration, so that RTD is considered part of the MN disease spectrum. Based on previous findings demonstrating energy dysmetabolism and mitochondrial impairment in RTD induced Pluripotent Stem cells (iPSCs) and iPSC-derived MNs, here we address the involvement of intrinsic apoptotic pathways in disease pathogenesis using these patient-specific in vitro models by combined ultrastructural and confocal analyses. We show impaired neuronal survival of RTD iPSCs and MNs. Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) documents severe alterations in patients' cells, including deranged mitochondrial ultrastructure, and altered plasma membrane and nuclear organization. Occurrence of aberrantly activated apoptosis is confirmed by immunofluorescence and TUNEL assays. Overall, our work provides evidence of a role played by mitochondrial dysfunction in RTD, and identifies neuronal apoptosis as a contributing event in disease pathogenesis, indicating intrinsic apoptosis pathways as possible relevant targets for more effective therapeutical approaches.
(© 2024. The Author(s).)
Databáze: MEDLINE
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