1. Genome-wide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown–Vialetto disease that is partially rescued by riboflavin
- Author
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Agnese Ramirez, Giacomo P. Comi, Alessia Niceforo, Claudia Compagnucci, Andreina Bordoni, Francesco Fortunato, Stefania Corti, Sabrina Salani, Nereo Bresolin, Enrico Bertini, Valentina Melzi, Federica Rizzo, and Monica Nizzardo
- Subjects
0301 basic medicine ,Neurofilament ,Hearing Loss, Sensorineural ,Riboflavin ,Bulbar Palsy, Progressive ,Induced Pluripotent Stem Cells ,Neuronal Outgrowth ,Biology ,Article ,Transcriptome ,03 medical and health sciences ,medicine ,Autophagy ,Humans ,Axon ,Induced pluripotent stem cell ,Cells, Cultured ,Cytoskeleton ,Regulation of gene expression ,Motor Neurons ,Multidisciplinary ,Gene Expression Profiling ,Neurodegeneration ,RNA ,High-Throughput Nucleotide Sequencing ,Cell Differentiation ,Motor neuron ,medicine.disease ,Cell biology ,Mitochondria ,030104 developmental biology ,medicine.anatomical_structure ,Neuroprotective Agents ,Biochemistry ,Gene Expression Regulation ,Dietary Supplements ,Energy Metabolism ,Genome-Wide Association Study - Abstract
Riboflavin is essential in numerous cellular oxidation/reduction reactions but is not synthesized by mammalian cells. Riboflavin absorption occurs through the human riboflavin transporters RFVT1 and RFVT3 in the intestine and RFVT2 in the brain. Mutations in these genes are causative for the Brown–Vialetto–Van Laere (BVVL), childhood-onset syndrome characterized by a variety of cranial nerve palsies as well as by spinal cord motor neuron (MN) degeneration. Why mutations in RFVTs result in a neural cell–selective disorder is unclear. As a novel tool to gain insights into the pathomechanisms underlying the disease, we generated MNs from induced pluripotent stem cells (iPSCs) derived from BVVL patients as an in vitro disease model. BVVL-MNs explained a reduction in axon elongation, partially improved by riboflavin supplementation. RNA sequencing profiles and protein studies of the cytoskeletal structures showed a perturbation in the neurofilament composition in BVVL-MNs. Furthermore, exploring the autophagy–lysosome pathway, we observed a reduced autophagic/mitophagic flux in patient MNs. These features represent emerging pathogenetic mechanisms in BVVL-associated neurodegeneration, partially rescued by riboflavin supplementation. Our data showed that this therapeutic strategy could have some limits in rescuing all of the disease features, suggesting the need to develop complementary novel therapeutic strategies.
- Published
- 2017