INVESTIGADORES
SOCIAS Sergio Benjamin
artículos
Título:
CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects
Autor/es:
GONZÁLEZ-LIZÁRRAGA, FLORENCIA; PLOPER, DIEGO; ÁVILA, CÉSAR L.; SOCÍAS, SERGIO B.; DOS-SANTOS-PEREIRA, MAURICIO; MACHÍN, BELÉN; DEL-BEL, ELAINE; MICHEL, PATRICK PIERRE; PIETRASANTA, LÍA I.; RAISMAN-VOZARI, RITA; CHEHÍN, ROSANA
Revista:
Scientific Reports
Editorial:
Nature Research
Referencias:
Lugar: Londres; Año: 2020 vol. 10
Resumen:
Parkinson´s disease (PD) is a neurodegenerative disorder for which only symptomatic treatments are available. Repurposing drugs that target α-synuclein aggregation, considered one of the main drivers of PD progression, could accelerate the development of disease-modifying therapies. In this work, we focused on chemically modified tetracycline 3 (CMT-3), a derivative with reduced antibiotic activity that crosses the blood?brain barrier and is pharmacologically safe. We found that CMT-3 inhibited α-synuclein amyloid aggregation and led to the formation of non-toxic molecular species, unlike minocycline. Furthermore, CMT-3 disassembled preformed α-synuclein amyloid fibrils into smaller fragments that were unable to seed in subsequent aggregation reactions. Most interestingly, disaggregated species were non-toxic and less inflammogenic on brain microglial cells. Finally, we modelled the interactions between CMT-3 and α-synuclein aggregates by molecular simulations. In this way, we propose a mechanism for fibril disassembly. Our results place CMT-3 as a potential disease modifier for PD and possibly other synucleinopathies.