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

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

Chicago

Congreso; Neuroscience 2019 . Annual meeting. Society for Neuroscience SFN; 2019

Society for Neuroscience (USA)

Abstract: Parkinson?s disease (PD) is a progressive neurodegenerative illness with age being themain risk factor for its development. The increase in longevity in most Western countriesimposes the urgency of finding a disease-modifying approach for its treatment. Severalpromising molecules targeting PD pathogenic pathways have been proposed but with limitedsuccess. Targeted pathways include notably those regulating alpha-synuclein aggregation,oxidative stress and neuroinflammation. Due to the multifactorial characteristics of the disease, amultitarget drug with efficient activity against these processes is required. With this in mind, wepreviously demonstrated that the tetracycline doxycycline (DOX) reshapes oligomeric species ofthe PD protein alpha-synuclein reducing their toxicity, seeding capacity and propensity to formtoxic fibrillary species. In addition, DOX showed anti-inflammatory and neuroprotective effectsin PD models. However, the antibiotic activity of DOX represents a possible hurdle for itsrepositioning in long-term treatments. Thus, we sought to find a non-antibiotic DOX analog withpotent anti-amyloidogenic properties, making this drug an ideal candidate for repurposing totreat PD and conceivably other amyloid-associated disorders. In order to detect putative antiamyloidogenicready to use molecules, we used chemicoinformatic methods to extract a novelstructural motif capable of interacting with cross-beta structures (Cbeta-IM) and screened anumber of pre-existing compounds using this strategy. Incyclinide was selected amongtetracyclines because i) it contains this motif in a planar structure, ii) crosses the BBB, and iii) isavailable for repurposing. Using a combination of biophysical techniques (fluorescence and infrared spectroscopy, electron microscopy, small-angle X-Ray scattering) together with cellbiology approaches, we characterized its impact against alpha-synuclein toxic aggregates.Incyclinide had an exceptional ability to reshape alpha-synuclein oligomers towards less toxicand non-seeding species. Moreover, Incyclinide was able to disrupt mature fibrils and was moreefficient than DOX at inhibiting neuroinflammatory processes initiated by microglial cells. Theanti-amyloidogenic and anti-inflammatory properties of Incyclinide, together with its ability tocross the BBB, position Incyclinide as an ideal drug to be repurposed in PD and possibly in otheramyloid-associated diseases. We also propose the Cbeta-IM as a molecular signature to beexploited for identifying novel drugs of interest for neuroprotection in PD.