| Autor: |
González-Lizárraga F; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina., Ploper D; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina., Ávila CL; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina., Socías SB; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina., Dos-Santos-Pereira M; Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil., Machín B; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina., Del-Bel E; Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil., Michel PP; Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université UM75, Paris, France., Pietrasanta LI; Departamento de Física-Instituto de Física de Buenos Aires (IFIBA, UBA-CONICET) and Centro de Microscopías Avanzadas (CMA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina., Raisman-Vozari R; Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université UM75, Paris, France. ritaraisman@gmail.com., Chehín R; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina. rosanachehin@gmail.com. |
| Abstrakt: |
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. |
