Incyclinide, a non-antibiotic tetracycline, prevents alpha-synuclein aggregation and disrupts fibrillary forms of the protein

RAISMAN- VOZARI, R; GONZALEZ-LIZARRAGA, MF; PLOPER, D; SOCIAS, SB; AVILA, CL; MICHEL, P; CHEHIN, R

Chicago

Congreso; Neuroscience 2019; 2019

Society for Neuroscience

Parkinson?s disease (PD) is a progressive neurodegenerative illness with age being the main risk factor for its development. The increase in longevity in most Western countries imposes the urgency of finding a disease-modifying approach for its treatment. Several promising molecules targeting PD pathogenic pathways have been proposed but with limited success. Targeted pathways include notably those regulating alpha-synuclein aggregation, oxidative stress and neuroinflammation. Due to the multifactorial characteristics of the disease, a multitarget drug with efficient activity against these processes is required. With this in mind, we previously demonstrated that the tetracycline doxycycline (DOX) reshapes oligomeric species of the PD protein alpha-synuclein reducing their toxicity, seeding capacity and propensity to form toxic fibrillary species. In addition, DOX showed anti-inflammatory and neuroprotective effects in PD models. However, the antibiotic activity of DOX represents a possible hurdle for its repositioning in long-term treatments. Thus, we sought to find a non-antibiotic DOX analog with potent anti-amyloidogenic properties, making this drug an ideal candidate for repurposing to treat PD and conceivably other amyloid-associated disorders. In order to detect putative anti-amyloidogenic ready to use molecules, we used chemicoinformatic methods to extract a novel structural motif capable of interacting with cross-beta structures (Cbeta-IM) 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) crosses the BBB, and iii) is available for repurposing. Using a combination of biophysical techniques (fluorescence and infrared spectroscopy, electron microscopy, small-angle X-Ray scattering) together with cell biology approaches, we characterized its impact against alpha-synuclein toxic aggregates.Incyclinide had an exceptional ability to reshape alpha-synuclein 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 initiated by microglial cells. The anti-amyloidogenic and anti-inflammatory properties of Incyclinide, 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 the Cbeta-IM as a molecular signature to be exploited for identifying novel drugs of interest for neuroprotection in PD.