{
  "abstract": "Introduction\n\nHyperphosphorylated Tau accumulation drives neurodegeneration in Alzheimer's disease (AD), but mechanisms linking impaired Tau ubiquitination to disease progression remain incompletely defined.Methods\n\nWe integrated Drosophila RNAi screening, human AD datasets, cellular assays, and mouse tauopathy models to evaluate arrestin domain-containing 4 (ARRDC4) in Tau pathology. ARRDC4-dependent regulation of Tau ubiquitination was examined using proteomics, proximity labeling, co-immunoprecipitation, BiFC, domain mapping, genetic suppression, and small-molecule interference.Results\n\nARRDC4 was upregulated in AD-relevant human and animal datasets and correlated with Tau burden. ARRDC4 overexpression promoted Tau phosphorylation, self-association, seeded aggregation, secretion, and inflammatory activation. Mechanistically, ARRDC4 brought Tau and USP14 into proximity, suppressing Tau ubiquitination. Genetic ARRDC4 deficiency or pharmacological disruption of the ARRDC4-USP14 interface restored Tau ubiquitination and ameliorated Tau pathology, neuroinflammation, neuronal injury, and behavioral deficits across cellular, Drosophila, and mouse models.Discussion\n\nARRDC4 is a regulator of Tau proteostasis and a potential therapeutic target for Tau-associated AD pathology.",
  "abstract_shown": true,
  "affiliations": [
    "State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Cell and Developmental Biology at School of Life Sciences, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai, China.",
    "Shanghai Engineering Research Center of Ultra-precision Optical Manufacturing, College of Future Information Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jiaqi Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Bing-Wen Xiao"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaohan Mai"
    },
    {
      "affs": [
        0
      ],
      "name": "Yi-Chun Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yiyan Fei"
    },
    {
      "affs": [
        0
      ],
      "name": "Yang Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Steven X Hou"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8w7vhrw30zcfh.bib",
  "cited_by": 0,
  "doi": "10.1002/alz.71926",
  "fulltext_url": "https://europepmc.org/articles/PMC13719805",
  "id": "8w7vhrw30zcfh",
  "issns": [
    "1552-5260",
    "1552-5279"
  ],
  "landing_url": "https://europepmc.org/article/MED/42957973",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7224915047",
  "pdf_url": "https://europepmc.org/articles/PMC13719805?pdf=render",
  "pmcid": "PMC13719805",
  "pmid": "42957973",
  "published": "2026-10-01",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/8w7vhrw30zcfh.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:44Z",
      "native_id": "MED:42957973",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42957973"
    },
    {
      "first_seen": "2026-11-02T12:23:42Z",
      "native_id": "PMC13719805",
      "source": "pmc",
      "url": "https://doi.org/10.1002/alz.71926"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.",
  "title_text": "ARRDC4 drives Tau pathology via USP14-mediated deubiquitination and acts as a novel therapeutic target in Alzheimer's disease.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:48Z",
  "url": "https://research.draconitic.com/paper/8w7vhrw30zcfh",
  "venue": "Alzheimer's & dementia : the journal of the Alzheimer's Association",
  "versions": []
}