CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects

• Published in: Scientific reports 2020-11, Vol.10 (1), p.20258, Article 20258
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/1647/2204/1262; 631/1647/328/1649; 631/1647/328/1978; 631/1647/328/2082; 631/57; 631/57/2266; 631/57/2269; 631/80/470/2284; 692/699/375/1718; Aggregates; alpha-Synuclein - metabolism; alpha-Synuclein - toxicity; Amyloid; Blood-brain barrier; Drug Repositioning; Fibrils; Human health and pathology; Humanities and Social Sciences; Humans; Inflammation - chemically induced; Life Sciences; Medical treatment; Microglia; Minocycline; Movement disorders; multidisciplinary; Neurodegenerative diseases; Parkinson Disease - drug therapy; Parkinson's disease; Protein Aggregates; Science; Science (multidisciplinary); Synuclein; Tetracyclines - pharmacology; Tetracyclines - therapeutic use
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-76927-0

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.