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

• DOI: 10.1073/pnas.0903011106
• Publication Date: 2009-07-07T01:54:03Z
• Authors: J. Paul Simons; Raya Al-Shawi; Shane Minogue; Mark G. Waugh; Claudia Wiedemann; Stylianos Evangelou; Andrzej Loesch; Talvinder S. Sihra; Rosalind King; Thomas T. Warner; J. Justin Hsuan
• Keywords: Mice, Knockout; 0303 health sciences; Alanine Transaminase; Axons; 3. Good health; Minor Histocompatibility Antigens; Mice; Phosphotransferases (Alcohol Group Acceptor); 03 medical and health sciences; Spinal Cord; Nerve Degeneration; Animals; Aspartate Aminotransferases; Blood Chemical Analysis; Signal Transduction

Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase phosphatase activities. Although many roles of kinases have been identified in cultured cell lines, transgenic animal studies unexpected insight into the vivo functions specific 3- 5-kinases, but no mammalian 4-kinase (PI4K) knockout has previously reported. Prior using cells implicated PI4K2alpha isozyme diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, regulated secretion. We now show that despite these important mice lacking activity initially appear normal. However, adult Pi4k2a(GT/GT) animals develop a progressive neurological disease characterized tremor, limb weakness, urinary incontinence, premature mortality. Histological analysis aged revealed lipofuscin-like deposition gliosis cerebellum, loss Purkinje cells. Peripheral nerves essentially normal, massive axonal degeneration was found spinal cord both ascending descending tracts. These results reveal undescribed role for aberrant resembles autosomal recessive hereditary spastic paraplegia.