{
  "abstract": "This study shows that Parkinson’s disease–associated kinase LRRK2 is activated by inhibition of PIKfyve, which metabolizes phosphatidylinositol 3-phosphate, and reveals a novel mechanism of LRRK2 activation that requires interaction with phosphatidylinositol 3-phosphate, as well as CASM and Rab. LRRK2 is a Parkinson’s disease–associated kinase that phosphorylates Rab GTPases. Hyperactivation of LRRK2, which is thought to cause Parkinson’s disease, occurs on stressed endolysosomal membranes via conjugation of ATG8 to single membranes (CASM) and Rab, whereas the involvement of specific membrane lipids remained unclear. Here, we found that the inhibition of PIKfyve that metabolizes phosphatidylinositol 3-phosphate (PI3P) induces hyperactivation of LRRK2 and that additional inhibition of the class III phosphoinositide 3-kinase that generates PI3P suppressed LRRK2 hyperactivation. Cellular PI3P levels were indeed elevated when LRRK2 was activated. CASM-induced activation of LRRK2, but not CASM itself, was suppressed by phosphoinositide 3-kinase inhibitors, whereas inhibition of CASM or Rab12/Rab29 suppressed LRRK2 activation induced by PIKfyve inhibitors. LRRK2 and phospho-Rab10 were colocalized with PI3P on LAMP1-positive enlarged vacuoles, and LRRK2 directly bound PI3P in vitro via its N-terminal positively charged amino acids. Together, we propose an updated mechanism of LRRK2 hyperactivation that simultaneously requires CASM, Rab, and PI3P-rich membranes.",
  "abstract_shown": true,
  "affiliations": [
    "1 https://ror.org/057zh3y96 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan",
    "2 Lipidome Lab Co., Ltd, Akita, Japan",
    "3 https://ror.org/026k5mg93 Norwich Medical School, University of East Anglia , Norwich, UK",
    "4 Artificial Intelligence Research Center (AIRC), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan",
    "1 https://ror.org/057zh3y96 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan 5 Department of Dementia Inclusion and Therapeutics, The University of Tokyo Hospital, Tokyo, Japan 6 https://ror.org/0254bmq54 National Center of Neurology and Psychiatry , Tokyo, Japan"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Tomoki Kuwahara"
    },
    {
      "affs": [
        0
      ],
      "name": "Gen Yoshii"
    },
    {
      "affs": [
        0
      ],
      "name": "Maria Sakurai"
    },
    {
      "affs": [
        0
      ],
      "name": "Shoichi Suenaga"
    },
    {
      "affs": [
        1
      ],
      "name": "Hiroki Nakanishi"
    },
    {
      "affs": [
        2
      ],
      "name": "Matthew Jefferson"
    },
    {
      "affs": [
        2
      ],
      "name": "Thomas Wileman"
    },
    {
      "affs": [
        3
      ],
      "name": "Kentaro Tomii"
    },
    {
      "affs": [
        4
      ],
      "name": "Takeshi Iwatsubo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/36b5sjw1fgm1j.bib",
  "cited_by": 1,
  "doi": "10.26508/lsa.202603939",
  "fulltext_url": "https://www.life-science-alliance.org/lookup/doi/10.26508/lsa.202603939",
  "id": "36b5sjw1fgm1j",
  "issns": [
    "2575-1077"
  ],
  "landing_url": "https://doi.org/10.26508/lsa.202603939",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "lcc",
      "R"
    ],
    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
    ]
  ],
  "openalex": "W7115890997",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-07",
  "publisher": "Life Science Alliance LLC",
  "ris": "https://research.draconitic.com/paper/36b5sjw1fgm1j.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T14:21:06Z",
      "native_id": "c904bedad2774b089c9bc774d0419f9f",
      "source": "doaj",
      "url": "https://doi.org/10.26508/lsa.202603939"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Parkinson's Disease Mechanisms and Treatments",
      "subfield": "neurology"
    }
  ],
  "title": "PIKfyve inhibition induces LRRK2 activation through phosphatidylinositol 3-phosphate and CASM",
  "title_text": "PIKfyve inhibition induces LRRK2 activation through phosphatidylinositol 3-phosphate and CASM",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T14:20:33Z",
  "url": "https://research.draconitic.com/paper/36b5sjw1fgm1j",
  "venue": "Life Science Alliance",
  "versions": []
}