The non-antibiotic tetracycline CMT-3 inhibits a-synuclein aggregation, seeding and neuroinflammation

RAISMAN VOZARI R.; GONZALES LIZARRAGA, MF; PLOPER D.; AVILA C.; SOCIAS SB.; DOS-SANTOS-PEREIRA, MAURICIO; MACHÍN B.; DEL-BEL E.; MICHEL P.; PIETRASANTA L.; CHEHÍN R.

Congreso; FENS Virtual Forum 2020; 2020

Federation of European Neuroscience Societies

Repositioning of doxycycline (DOX) as a multitarget disease-modifying drug for Parkinson disease (PD) has been proposed based on its ability to protect dopaminergic neurons and prevent neuroinflammation, oxidative stress and α-synuclein toxic aggregation. However, the antibiotic activity of this tetracycline represents a hurdle for long-term treatments. Here, we focused on chemically modified tetracycline 3 (CMT-3), a DOX analog with a low antibiotic activity that crosses the blood-brain barrier (BBB) and is ready for repurposing. We demonstrate that CMT-3 efficiently inhibited α-synuclein amyloid aggregation by binding and reshaping early aggregates into morphologically and structurally different species with less toxicity. Furthermore, CMT-3 even disassembled preformed α-synuclein fibrils into smaller species that were unable to seed in subsequent aggregation reactions, disrupt membrane integrity, nor exhibit cellular toxicity. Additionally, these species triggered a decreased inflammatory response in primary microglia cultures compared to α-synuclein amyloid fibrils. Finally, molecular dynamics simulations suggested the position as well as residues involved in the interaction between CMT-3 and α-synuclein fibrils. Our findings also provide evidence for a link between specific substituents in tetracyclines and the ability to inhibit α-synuclein aggregation, offering a possible explanation for the failure of minocycline in PD clinical trials. Results presented herein highlight the potential of CMT-3 as a candidate for further consideration and clinical evaluation as a disease modifier in PD and other synucleinopathies