Neurochemistry and Neuropharmacology
Author: María Laura Guayán | Email: mlauraguayan@gmail.com
María Laura Guayán 1°, Diego Ploper 1°, Rodrigo Tomas Grau 1°, Bruno Figadère 3°, Rose Clémence 3°, Rita Raisman Vozari 2°, Rosana Chehín 1°
1° Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA)
2° Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière
3° BioCIS, Université Paris-Saclay, CNRS
Parkinson’s disease (PD) is a chronic neurodegenerative disorder that affects millions worldwide. It involves the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, and is thought to be triggered by the presence of toxic amyloid aggregates of α-Synuclein (αS), predominantly phosphorylated at Serine 129 (S129). Currently, no drug is able to stop, nor slow down, neuronal death in PD. Several tetracyclines (TCs) (Minocycline, Doxycycline, Chlortetracycline and Demeclocycline) have shown neuroprotective effects in preclinical models, but their antibacterial activity limits their use. Therefore, modified TCs without antibiotic action were designed and screened for their ability to inhibit αS aggregation. Here we further evaluate one of the best inhibitors, ChloRed2 (CR2), derived from Chlortetracycline. In SH-SY5Y cells, a PD cellular model, CR2 showed no toxicity and conserved important antioxidant properties present in TCs. In addition, in transgenic SH-SY5Y-αS-RFP cells, CR2 inhibited the ability of pre-formed αS fibrils (αS-PFF) to seed endogenous αS. Surprisingly, CR2 also inhibited the phosphorylation of αS at S129 and lysosomal stress induced by αS-PFF. These results poise CR2 as an attractive drug candidate for further in vivo tests and uncover hidden properties of TCs that could be harnessed for further drug development.