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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder for which only symptomatic treatments are available
We compared the impact of chemically modified tetracycline 3 (CMT-3), DOX and MINO on α-synuclein amyloid aggregation by monitoring fluorescence intensity of the amyloid-specific probe Thioflavin T (ThT) (Fig. 1b)
chemically modified tetracyclines (CMTs)-3 is a tetracycline derivative with reduced antibiotic activity that is ready to enter in phase II clinical trials
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder for which only symptomatic treatments are available. To efficiently modify the course of neurodegeneration in PD, an ideal drug should be capable of interfering with α-synuclein aggregation, halting the generation of toxic species, disassembling preformed toxic aggregates, and inhibiting neuroinflammatory processes. Such a multi-target compound should possess the ability to cross the blood–brain barrier (BBB), often an essential obstacle in the pharmaceutical development of medications targeting the central nervous system. Minocycline (MINO) has drawn a great deal of attention since this tetracycline was reported to protect from PD-neurodegeneration in preclinical models of the d isease[19,22,23] On this basis, MINO was included in a pilot clinical trial for early PD. This finding revived interest in therapeutic use of tetracyclines for P D26
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