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<p>The increasing prevalence of Parkinson’s disease (PD) requires innovative multi-targeted disease-modifying 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 <i>in vitro</i> and <i>in vivo</i>. 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.</p>

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DDOX expands the repertoire of tetracyclines for Parkinson’s disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • María del Milagro Teran,
  • Rodrigo Hernán Tomas-Grau,
  • Estefanía Silvana Soliz-Santander,
  • María Laura Guayán,
  • Valentina Budeguer Isa,
  • Alvaro Luna Mercado,
  • Cesar Luis Avila,
  • Bernardo Sosa-Padilla,
  • Hernán Cruz,
  • Ismaila Ciss,
  • Pierre Besnault,
  • Sergio Benjamín Socias,
  • Esteban Vera Pingitore,
  • Laurent Ferrié,
  • Rita Raisman-Vozari,
  • Patrick Pierre Michel,
  • Bruno Figadère,
  • Rosana Nieves Chehín,
  • Diego Ploper

摘要

The increasing prevalence of Parkinson’s disease (PD) requires innovative multi-targeted disease-modifying 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.