ANTI-AGGREGATION AND DISAGGREGATION PROPERTIES OF THE NONANTIBIOTIC TETRACYCLINE INCYCLINIDE AGAINST THE PARKINSON DISEASE PROTEIN ALPHA-SYNUCLEIN

GONZALES LIZARRAGA, MF; AVILA C.; PLOPER D.; SOCIAS, S.B.; MICHEL, P.; RAISMAN VOZARI R.; PIETRASANTA L.; CHEHÍN R.

Lima

Congreso; Biophysical Society Thematic Meetings: Revisiting the Central Dogma of Molecular Biology at the Single-Molecule Level; 2019

Biophysical Society

Objectives: Parkinson?s disease (PD) is a progressive neurodegenerative condition with agebeing the main risk factor for its development. This disease has a multifactorial basis and amulti-target treatment is required. The escalating cost of developing new compounds hasreinvigorated interest in drug repositioning to accelerate bench to bedside transition. With this inmind, we previously demonstrated that the tetracycline doxycycline (DOX) reshapes oligomericspecies of the Parkinson disease protein alpha-synuclein (aS) reducing their toxicity, seedingcapacity and propensity to form toxic fibrillar species. However, the antibiotic activity of DOXrepresents a possible hurdle for its repositioning in long-term treatments. Thus, we sought out tofind a non-antibiotic DOX analogue with potent anti-amyloidogenic properties, making this drugan ideal candidate for repurposing to treat PD and conceivably other amyloid-associateddisorders. Methods: In order to detect putative anti-amyloidogenic ready to use molecules, weused chemioinformatic techniques to extract a novel structural motif (Cb-IM) capable ofinteracting with cross-b structures and screened a number of pre-existing compounds using thisstrategy. Incyclinide was selected among tetracyclines because: i) it contains this motif in aplanar structure, ii) passes the BBB, and iii) is ready for repurposing. Using a combination ofbiophysical techniques (fluorescence and infrared spectroscopy, scattering second order, electronmicroscopy, atomic force microscopy) together with cell biology approaches, we characterizedits impact against aS toxic aggregates. Results: Incyclinide had an exceptional ability to reshapeaS oligomers towards less toxic and non-seeding species. Moreover, Incyclinide was able todisrupt mature fibrils and was more efficient than DOX at inhibiting neuroinflammatoryprocesses. Conclusion: The anti-amyloidogenic and anti-neuroinflammatory properties ofIncyclinide, together with its ability to cross the BBB, position Incyclinide as an ideal drug to berepurposed in PD and possibly in other amyloid-associated diseases.