{
  "abstract": "Prion diseases (PrDs) are fatal neurodegenerative disorders characterized by the accumulation of misfolded prion protein (PrPSc) and progressive impairment of protein quality-control systems. Lysosomal dysfunction and defective autophagic flux contribute to PrPSc accumulation, but the upstream regulatory mechanisms remain incompletely defined. In this study, we investigated the regulatory role of miR-148a-3p during prion infection. We found that miR-148a-3p expression is markedly increased in ME7- and 139A-infected mouse brains and prion-infected SMB-S15 cells. Dual-luciferase assays confirmed that miR-148a-3p directly targets the PRNP 3′UTR, negatively regulating cellular PrP expression. In prion-infected cells, inhibition of miR-148a-3p reduced proteinase K (PK)-resistant PrP (PrPres), delayed RT-QuIC conversion, and decreased PMCA-amplified PrPres. Through bioinformatic prediction and experimental validation, we identified ATP6AP2, a V-ATPase-associated regulator of lysosomal acidification, as a high-confidence target of miR-148a-3p. ATP6AP2 expression was significantly decreased in sCJD transcriptomic data, scrapie-infected mouse brains, and prion-infected cells. Importantly, inhibition of miR-148a-3p restored ATP6AP2 expression, which improved lysosomal acidification and alleviated impaired autophagic flux. Furthermore, overexpression of ATP6AP2 directly reduced PrPSc accumulation in SMB-S15 cells and diminished prion seeding capacities in RT-QuIC and PMCA assays. These findings identify miR-148a-3p as an upstream regulator of ATP6AP2-dependent lysosomal dysfunction in prion infection. Inhibition of miR-148a-3p may restore lysosomal clearance capacity and reduce PrPSc accumulation, suggesting a potential regulatory strategy for PrDs.",
  "abstract_shown": true,
  "affiliations": [
    "National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory for Medical Virology and Viral Diseases, Beijing Key Laboratory of Viral Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention & Chinese Academy of Preventive Medicine, Beijing 102206, China",
    "Shanghai Institute of Infectious Disease and Biosafety, Shanghai 200003, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rui Xu",
      "orcid": "0009-0000-6770-6073"
    },
    {
      "affs": [
        0
      ],
      "name": "Cao Chen",
      "orcid": "0000-0002-5193-9283"
    },
    {
      "affs": [
        0
      ],
      "name": "Tong-Xin Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "Ju-Zheng Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Xing-Hao Zhai"
    },
    {
      "affs": [
        0
      ],
      "name": "Bing Xu",
      "orcid": "0000-0001-7914-6528"
    },
    {
      "affs": [
        0
      ],
      "name": "Ru-Han A",
      "orcid": "0000-0003-1399-6540"
    },
    {
      "affs": [
        0
      ],
      "name": "Xue-Qin Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Fang-Fan Ning"
    },
    {
      "affs": [
        0
      ],
      "name": "Dong-Lin Liang"
    },
    {
      "affs": [
        0
      ],
      "name": "Run-Dong Cao"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Li-Ping Gao",
      "orcid": "0000-0002-7022-0418"
    },
    {
      "affs": [
        0
      ],
      "name": "Kang Xiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Qi Shi"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiao-Ping Dong",
      "orcid": "0000-0002-1566-8447"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5aj802z9vyytf.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219524",
  "fulltext_url": null,
  "id": "5aj802z9vyytf",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9524",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Prion Diseases and Protein Misfolding"
    ]
  ],
  "openalex": "W7223865251",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-24",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/5aj802z9vyytf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:57Z",
      "native_id": "10.3390/ijms27219524",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9524"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Prion Diseases and Protein Misfolding",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Inhibition of miR-148a-3p Ameliorates Prion Accumulation by Restoring ATP6AP2-Mediated Lysosomal Acidification",
  "title_text": "Inhibition of miR-148a-3p Ameliorates Prion Accumulation by Restoring ATP6AP2-Mediated Lysosomal Acidification",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:57Z",
  "url": "https://research.draconitic.com/paper/5aj802z9vyytf",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}