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Loss of phosphatidylinositol 4-kinase 2 alpha activity causes late onset degeneration of spinal cord axons

Simons, JP; Al-Shawi, R; Minogue, S; Waugh, MG; Wiedemann, C; Evangelou, S; Loesch, A; ... Hsuan, JJ; + view all (2009) Loss of phosphatidylinositol 4-kinase 2 alpha activity causes late onset degeneration of spinal cord axons. P NATL ACAD SCI USA , 106 (28) 11535 - 11539. 10.1073/pnas.0903011106. Gold open access

Abstract

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 alpha 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 alpha kinase activity initially appear normal. However, adult Pi4k2a(GT/GT) animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged Pi4k2a(GT/GT) 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.

Type: Article
Title: Loss of phosphatidylinositol 4-kinase 2 alpha activity causes late onset degeneration of spinal cord axons
Open access status: An open access publication
DOI: 10.1073/pnas.0903011106
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC27106...
Keywords: genetrap, hereditary spastic paraplegia, phosphoinositide, lipofuscin, neurodegeneration, HEREDITARY SPASTIC PARAPLEGIA, DEFICIENT MICE, TRANSPORT, TRAFFICKING, ENZYMES, MECHANISMS, LIPOFUSCIN, COMPLEXES, MOTILITY, ISOFORMS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: http://discovery.ucl.ac.uk/id/eprint/177896
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