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

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.

Highly reusable invertase biocatalyst: Biological fibrils functionalized by photocrosslinking.

Here we report a novel strategy for the immobilization of invertase using amyloid-like fibrils as a support. Optimal conditions to get Tyr-Tyr covalent binding between invertase and the support were determined using a photocrosslinking approach. The biological fibrils with invertase activity turn into microstructured catalysts according to electron microscopy outcomes. Thermal and storage stability as well as optimal pH and temperature of the enzyme were conserved. Moreover, the immobilized enzyme recovered by low g-force centrifugation retained 83% of its initial enzymatic activity after 15 reuse cycles. Considering that enzyme cost is the most significant part of the overall fee of enzymatic biomass conversion, the highly efficient recovery/reuse strategy described herein becomes relevant. Besides, it can also be applied to the immobilization of other enzymes for industrial biocatalysis.