{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "name": "María del Milagro Teran"
    },
    {
      "name": "Rodrigo Hernán Tomas-Grau"
    },
    {
      "name": "Estefanía Silvana Soliz-Santander"
    },
    {
      "name": "María Laura Guayán"
    },
    {
      "name": "Valentina Budeguer Isa"
    },
    {
      "name": "Alvaro Luna Mercado"
    },
    {
      "name": "Cesar Luis Avila"
    },
    {
      "name": "Bernardo Sosa-Padilla"
    },
    {
      "name": "Hernán Cruz"
    },
    {
      "name": "Ismaila Ciss"
    },
    {
      "name": "Pierre Besnault"
    },
    {
      "name": "Sergio Benjamín Socias"
    },
    {
      "name": "Esteban Vera Pingitore"
    },
    {
      "name": "Laurent Ferrié"
    },
    {
      "name": "Rita Raisman-Vozari"
    },
    {
      "name": "Patrick Pierre Michel"
    },
    {
      "name": "Bruno Figadère"
    },
    {
      "name": "Rosana Nieves Chehín"
    },
    {
      "name": "Diego Ploper"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/84exzsvx1ygyz.bib",
  "cited_by": 2,
  "doi": "10.1038/s41598-025-15991-w",
  "fulltext_url": null,
  "id": "84exzsvx1ygyz",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://hal.science/hal-05776012v1",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.sdv.mhep"
    ],
    [
      "hal",
      "1.sdv.neu"
    ],
    [
      "hal",
      "1.sdv.sp"
    ],
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      "hal",
      "2.sdv.neu.nb"
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    [
      "hal",
      "2.sdv.sp.pharma"
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    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
    ]
  ],
  "openalex": "W4415666798",
  "pdf_url": "https://hal.science/hal-05776012/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-02",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/84exzsvx1ygyz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:46Z",
      "native_id": "hal-05776012",
      "source": "hal",
      "url": "https://hal.science/hal-05776012v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "hal:1.sdv.neu",
      "subfield": "neuroscience"
    },
    {
      "field": "medicine",
      "origin": "hal:1.sdv.sp",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "DDOX expands the repertoire of tetracyclines for Parkinson’s disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils",
  "title_text": "DDOX expands the repertoire of tetracyclines for Parkinson’s disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:46Z",
  "url": "https://research.draconitic.com/paper/84exzsvx1ygyz",
  "venue": "Scientific Reports",
  "versions": []
}