DDOX expands the repertoire of tetracyclines for Parkinson’s disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils
Abstract
The increasing prevalence of Parkinson's disease (PD) requires innovative multi-targeted diseasemodifying therapies to counteract the toxicity associated with the amplification, propagation, and accumulation of alpha-synuclein (α-Syn) aggregates in the brain. Tetracyclines, particularly doxycycline, have demonstrated multimodal neuroprotective effects, both in vitro and in vivo. The non-antibiotic derivative of doxycycline 4-dedimethylamino-12a-deoxydoxycycline (DDOX), has been recently shown to rescue neurons from oxidative injury. Here, we demonstrate that DDOX showcases a diverse range of mechanisms targeting α-Syn aggregates. Notably, DDOX inhibited the aggregation of α-Syn and the seeding ability of α-Syn pre-formed fibrils (PFF) in biophysical and cellular assays. In addition, the compound ameliorated the relocalization of total and phospho-α-Syn, triggered by exogenous α-Syn PFF. Surprisingly, DDOX drastically mitigated lysosomal stress induced by these aggregates. Moreover, we determined that DDOX effectively impeded the internalization of fluorescently labeled α-Syn PFF. Biophysical techniques and molecular docking simulations suggest that DDOX binds to hydrophobic patches on α-Syn fibrils. Our findings reveal novel neuroprotective attributes of tetracyclines, wherein a direct extracellular interaction between DDOX and α-Syn aggregated species mitigates their intracellular impact. These results provide a promising foundation for DDOX, a drug that aims to interfere with the intracellular seeding, propagation and uptake of α-Syn fibrils in neurodegenerative conditions.
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BibTeX
@article{teran2026ddox,
title = {{DDOX expands the repertoire of tetracyclines for Parkinson’s disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils}},
author = {María del Milagro Teran and Rodrigo Hernán Tomas-Grau and Estefanía Silvana Soliz-Santander and María Laura Guayán and Valentina Budeguer Isa and Alvaro Luna Mercado and Cesar Luis Avila and Bernardo Sosa-Padilla and Hernán Cruz and Ismaila Ciss and Pierre Besnault and Sergio Benjamín Socias and Esteban Vera Pingitore and Laurent Ferrié and Rita Raisman-Vozari and Patrick Pierre Michel and Bruno Figadère and Rosana Nieves Chehín and Diego Ploper},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-025-15991-w},
url = {https://hal.science/hal-05776012v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - DDOX expands the repertoire of tetracyclines for Parkinson’s disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils
AU - María del Milagro Teran
AU - Rodrigo Hernán Tomas-Grau
AU - Estefanía Silvana Soliz-Santander
AU - María Laura Guayán
AU - Valentina Budeguer Isa
AU - Alvaro Luna Mercado
AU - Cesar Luis Avila
AU - Bernardo Sosa-Padilla
AU - Hernán Cruz
AU - Ismaila Ciss
AU - Pierre Besnault
AU - Sergio Benjamín Socias
AU - Esteban Vera Pingitore
AU - Laurent Ferrié
AU - Rita Raisman-Vozari
AU - Patrick Pierre Michel
AU - Bruno Figadère
AU - Rosana Nieves Chehín
AU - Diego Ploper
PY - 2026
DA - 2026/10/02
JO - Scientific Reports
DO - 10.1038/s41598-025-15991-w
UR - https://hal.science/hal-05776012v1
AB - The increasing prevalence of Parkinson's disease (PD) requires innovative multi-targeted diseasemodifying therapies to counteract the toxicity associated with the amplification, propagation, and accumulation of alpha-synuclein (α-Syn) aggregates in the brain. Tetracyclines, particularly doxycycline, have demonstrated multimodal neuroprotective effects, both in vitro and in vivo. The non-antibiotic derivative of doxycycline 4-dedimethylamino-12a-deoxydoxycycline (DDOX), has been recently shown to rescue neurons from oxidative injury. Here, we demonstrate that DDOX showcases a diverse range of mechanisms targeting α-Syn aggregates. Notably, DDOX inhibited the aggregation of α-Syn and the seeding ability of α-Syn pre-formed fibrils (PFF) in biophysical and cellular assays. In addition, the compound ameliorated the relocalization of total and phospho-α-Syn, triggered by exogenous α-Syn PFF. Surprisingly, DDOX drastically mitigated lysosomal stress induced by these aggregates. Moreover, we determined that DDOX effectively impeded the internalization of fluorescently labeled α-Syn PFF. Biophysical techniques and molecular docking simulations suggest that DDOX binds to hydrophobic patches on α-Syn fibrils. Our findings reveal novel neuroprotective attributes of tetracyclines, wherein a direct extracellular interaction between DDOX and α-Syn aggregated species mitigates their intracellular impact. These results provide a promising foundation for DDOX, a drug that aims to interfere with the intracellular seeding, propagation and uptake of α-Syn fibrils in neurodegenerative conditions.
SN - 2045-2322
ER -