CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects - Sorbonne Université Access content directly
Journal Articles Scientific Reports Year : 2020

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

Florencia González-Lizárraga
  • Function : Author
Diego Ploper
  • Function : Author
César L Ávila
  • Function : Author
Sergio B Socías
  • Function : Author
Mauricio Dos-Santos-Pereira
  • Function : Author
Belén Machín
  • Function : Author
Elaine Del-Bel
  • Function : Author
Lía I Pietrasanta
  • Function : Author
Rosana Chehín
  • Function : Author
  • PersonId : 1095604

Abstract

Abstract 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.
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Licence : CC BY - Attribution

Dates and versions

hal-04513319 , version 1 (20-03-2024)

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Florencia González-Lizárraga, Diego Ploper, César L Ávila, Sergio B Socías, Mauricio Dos-Santos-Pereira, et al.. CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects. Scientific Reports, 2020, 10 (1), pp.20258. ⟨10.1038/s41598-020-76927-0⟩. ⟨hal-04513319⟩
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