{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:57:37Z","timestamp":1784170657236,"version":"3.55.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"28","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,7,14]]},"abstract":"<jats:p>\n                    Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase and phosphatase activities. Although many signaling roles of PI kinases have been identified in cultured cell lines, transgenic animal studies have produced unexpected insight into the in vivo functions of specific PI 3- and 5-kinases, but no mammalian PI 4-kinase (PI4K) knockout has previously been reported. Prior studies using cultured cells implicated the PI4K2\u03b1 isozyme in diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, and regulated secretion. We now show that despite these important functions, mice lacking PI4K2\u03b1 kinase activity initially appear normal. However, adult\n                    <jats:italic>\n                      Pi4k2a\n                      <jats:sup>GT\/GT<\/jats:sup>\n                    <\/jats:italic>\n                    animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged\n                    <jats:italic>\n                      Pi4k2a\n                      <jats:sup>GT\/GT<\/jats:sup>\n                    <\/jats:italic>\n                    animals revealed lipofuscin-like deposition and gliosis in the cerebellum, and loss of Purkinje cells. Peripheral nerves are essentially normal, but massive axonal degeneration was found in the spinal cord in both ascending and descending tracts. These results reveal a previously undescribed role for aberrant PI signaling in neurological disease that resembles autosomal recessive hereditary spastic paraplegia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0903011106","type":"journal-article","created":{"date-parts":[[2009,7,6]],"date-time":"2009-07-06T21:54:03Z","timestamp":1246917243000},"page":"11535-11539","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":78,"title":["Loss of phosphatidylinositol 4-kinase 2\u03b1 activity causes late onset degeneration of spinal cord axons"],"prefix":"10.1073","volume":"106","author":[{"given":"J. Paul","family":"Simons","sequence":"first","affiliation":[{"name":"Division of Medicine,"},{"name":"Royal Free Centre for Biomedical Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raya","family":"Al-Shawi","sequence":"additional","affiliation":[{"name":"Division of Medicine,"},{"name":"Royal Free Centre for Biomedical Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Minogue","sequence":"additional","affiliation":[{"name":"Division of Medicine,"},{"name":"Royal Free Centre for Biomedical Science, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark G.","family":"Waugh","sequence":"additional","affiliation":[{"name":"Division of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Wiedemann","sequence":"additional","affiliation":[{"name":"Division of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stylianos","family":"Evangelou","sequence":"additional","affiliation":[{"name":"Division of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Loesch","sequence":"additional","affiliation":[{"name":"Division of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talvinder S.","family":"Sihra","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalind","family":"King","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, University College London Medical School, University College London, Rowland Hill Street, London NW3 2PF, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas T.","family":"Warner","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, University College London Medical School, University College London, Rowland Hill Street, London NW3 2PF, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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