| Autor: |
Elisa Maria Turco, Angela Maria Giada Giovenale, Laura Sireno, Martina Mazzoni, Alessandra Cammareri, Caterina Marchioretti, Laura Goracci, Alessandra Di Veroli, Daniel D'Andrea, Elena Marchesan, Barbara Torres, Laura Bernardini, Mariachiara Magnifico, Alessio Paone, Serena Rinaldo, Matteo Della Monica, Stefano D'Arrigo, Diana Postorivo, Anna Maria Nardone, Giuseppe Zampino, Roberta Onesimo, Chiara Leoni, Federico Caicci, Domenico Raimondo, Elena Binda, Laura Trobiani, Antonella De Jaco, Ada Maria Tata, Daniela Ferrari, Francesca Cutruzzolà, Gianluigi Mazzoccoli, Elena Ziviani, Maria Pennuto, Angelo Vescovi, Jessica Rosati |
| Rok vydání: |
2022 |
| DOI: |
10.21203/rs.3.rs-1489912/v2 |
| Popis: |
Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance. There is no therapy to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are not known. Here, we generated and characterized primary cells derived from four SMS patients, two carrying SMS-del and two carrying RAI1 point mutations, and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we show altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and a block of autophagic flux. SMS cells show increased cell death associated with mitochondrial pathology and reactive oxygen species production. Treatment with N-acetylcysteine reduces cell death and lipid accumulation, suggesting a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
