Repurposing doxycycline for synucleinopathies: remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species.
Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy per se is insufficient to account for neuroprotection. Herein we characterise novel targets of doxycycline describing the structural background supporting its effectiveness as a neuroprotector at subantibiotic doses. Our results show that doxycycline reshapes α-synuclein oligomers into off-pathway, high-molecular-weight species that do not evolve into fibrils. Off-pathway species present less hydrophobic surface than on-pathway oligomers and display different β-sheet structural arrangement. These structural changes affect the α-synuclein ability to destabilize biological membranes, cell viability, and formation of additional toxic species. Altogether, these mechanisms could act synergically giving novel targets for repurposing this drug.
Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT), Chacabuco 461 (T4000ILI) Tucumán, Argentina.|Institut National De La Santé Et De La Recherche Médicale, U 1127, CNRS, Unité Mixte De Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut Du Cerveau Et De La Moelle Epinière, ICM, Paris, France.
Florencia
F
González-Lizárraga
Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT), Chacabuco 461 (T4000ILI) Tucumán, Argentina.
Sergio B
SB
Socías
Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT), Chacabuco 461 (T4000ILI) Tucumán, Argentina.
César L
CL
Ávila
Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT), Chacabuco 461 (T4000ILI) Tucumán, Argentina.
Clarisa M
CM
Torres-Bugeau
Instituto de Física da Universidade de São Paulo - IFUSP, Rua do Matão, Travessa R, 187, São Paulo, Brazil.
Leandro R S
LR
Barbosa
Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Ocampo y Esmeralda, S2002LRK Rosario, Argentina.
Andres
A
Binolfi
Institut National De La Santé Et De La Recherche Médicale, U 1127, CNRS, Unité Mixte De Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut Du Cerveau Et De La Moelle Epinière, ICM, Paris, France.
Julia E
JE
Sepúlveda-Díaz
Department of Morphology, Physiology and Stomatology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil, Center of Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
Elaine
E
Del-Bel
Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Ocampo y Esmeralda, S2002LRK Rosario, Argentina.
Claudio O
CO
Fernandez
Laboratoire Croissance, Réparation et Régénération Tissulaires (CRRET), CNRS ERL 9215, Université Paris Est Créteil, Université Paris Est, F-94000, Créteil, France.
Dulce
D
Papy-Garcia
Instituto de Física da Universidade de São Paulo - IFUSP, Rua do Matão, Travessa R, 187, São Paulo, Brazil.
Rosangela
R
Itri
Institut National De La Santé Et De La Recherche Médicale, U 1127, CNRS, Unité Mixte De Recherche (UMR) 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut Du Cerveau Et De La Moelle Epinière, ICM, Paris, France.
Rita
R
Raisman-Vozari
Instituto Superior de Investigaciones Biológicas (INSIBIO), CCT-Tucumán and Instituto de Química Biológica Dr Bernabé Bloj (CONICET-UNT), Chacabuco 461 (T4000ILI) Tucumán, Argentina.
Rosana N
RN
Chehín
D045744:Cell Line, Tumor; D002470:Cell Survival; D004318:Doxycycline / Q000494:pharmacology* / Q000627:therapeutic use; D058492:Drug Repositioning; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D000072757:Protein Conformation, beta-Strand; D055503:Protein Multimerization; D017550:Spectroscopy, Fourier Transform Infrared; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
D066329:Protein Aggregates; D051844:alpha-Synuclein; D004318:Doxycycline