Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis
Rosana-Bristena Ionescu, Alexandra M. Nicaise, Julie A. Reisz, Eleanor C Williams, Pranathi Prasad, Cory M. Willis, Madalena B C Simões-Abade, Linda Sbarro, Monika Dzieciątkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti‐Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D’Alessandro, Stefano Pluchino
Abstract
Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.