Anti-aggregation and disaggregation properties of the non-antibiotic tetracycline Incyclinide against the Parkinson disease protein alpha-synuclein

FLORENCIA GONZÁLEZ LIZÁRRAGA; CESAR LUIS AVILA; DIEGO PLOPER; SERGIO B. SOCÍAS; PATRICK MICHEL; RITA RAISMAN-VOZARI; LÍA ISABEL PIETRASANTA ; ROSANA CHEHÍN

Lima

Congreso; Revisiting the Central Dogma of Molecular Biology at the Single-Molecule Level; 2019

Biophysical Society (BPS)

Objectives: Parkinson?s disease (PD) is a progressive neurodegenerative condition with age being the main risk factor for its development. Several promising molecules targeting PD pathogenic pathways were proposed but had limited success. Targeted pathways in- clude alpha-synuclein (aS) aggregation, oxidative stress, and neuroinflammation have all been explored individually as potential treatments. Due to the multifactorial basis of the disease, a multi-task drug with efficient activity against these three processes is required. The escalating cost of developing new compounds has reinvigorated interest in drug re- positioning to accelerate bench to bedside transition. With this in mind, we previously demonstrated that the tetracycline doxycycline (DOX) reshapes oligomeric species of the Parkinson disease (PD) protein alpha-synuclein (aS) reducing their toxicity, seeding capacity and propensity to form toxic fibrillar species. However, the antibiotic activity of DOX represents a possible hurdle for its repositioning in long-term treatments. Thus, we sought out to find a non-antibiotic DOX analogue with potent anti-amyloidogenic prop- erties, making this drug an ideal candidate for repurposing to treat PD and conceivably other amyloid-associated disorders.Methods: In order to detect putative anti-amyloidogenic ready to use molecules, we used chemioinformatic techniques to extract a novel structural motif (Cb-IM) capable of inter- acting with cross-b structures, and screened a number of pre-existing compounds using this strategy. Incyclinide was selected among tetracyclines because: i) it contains this motif in a planar structure, ii) passes the BBB, and iii) is ready for repurposing. Using a combination of biophysical techniques (fluorescence and infrared spectroscopy, scatter- ing second order, electron microscopy, atomic force microscopy) together with cell biology approaches, we characterized its impact against aS toxic aggregates.Results: Incyclinide had an exceptional ability to reshape aS oligomers towards less toxic and non-seeding species. Moreover, Incyclinide was able to disrupt mature fibrils and was more efficient than DOX at inhibiting neuroinflammatory processes, i.e., brain cellular responses that contribute to neurodegeneration.Conclusion: The anti-amyloidogenic and anti-neuroinflammatory properties of Incy- clinide, together with its ability to cross the BBB, position Incyclinide as an ideal drug to be repurposed in PD and possibly in other amyloid-associated diseases. We also propose a molecular mechanism that supports Cb-IM as a molecular signature to be exploited for identifying novel drugs of interest for neuroprotection.