CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects
| Autor: | César Ávila, Diego Ploper, Florencia González-Lizárraga, Belén Machín, Maurício dos-Santos-Pereira, Elaine Del-Bel, Patrick P. Michel, Rosana Chehín, Lía I. Pietrasanta, R. Raisman-Vozari, Sergio B. Socías |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Parkinson's disease Biophysics lcsh:Medicine Fibril Article Computational biophysics Atomic force microscopy Protein Aggregates medicine Humans lcsh:Science Synucleinopathies Inflammation Multidisciplinary Intrinsically disordered proteins Chemistry lcsh:R Drug Repositioning Parkinson Disease Minocycline Amyloid fibril nervous system diseases Confocal microscopy Tetracyclines Amyloid aggregation alpha-Synuclein α synuclein lcsh:Q Protein aggregation Scanning electron microscopy Transmission electron microscopy medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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