Loss of phosphatidylinositol 4-kinase 2α activity causes late onset degeneration of spinal cord axons
| Autor: | Shane Minogue, Claudia G. Wiedemann, Raya Al-Shawi, Stylianos Evangelou, J. Justin Hsuan, J. Paul Simons, Thomas T. Warner, Rosalind H.M. King, Talvinder S. Sihra, Mark G. Waugh, Andrzej Loesch |
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| Rok vydání: | 2009 |
| Předmět: |
Cerebellum
Hereditary spastic paraplegia Biology Minor Histocompatibility Antigens Mice chemistry.chemical_compound medicine Animals Aspartate Aminotransferases Phosphatidylinositol Kinase activity Mice Knockout Multidisciplinary Kinase Neurodegeneration Alanine Transaminase Biological Sciences medicine.disease Axons Cell biology Phosphotransferases (Alcohol Group Acceptor) medicine.anatomical_structure Spinal Cord Biochemistry chemistry Gliosis Nerve Degeneration Signal transduction medicine.symptom Blood Chemical Analysis Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 106:11535-11539 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0903011106 |
| Popis: | 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 PI4K2α 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 PI4K2α 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. |
| Databáze: | OpenAIRE |
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