Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons.
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 PI4K2alpha 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 PI4K2alpha 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.
Simons
J Paul
JP
Division of Medicine, Royal Free Centre for Biomedical Science, University College London Medical School, University College London, London NW3 2PF, United Kingdom.
Al-Shawi
Raya
R
Minogue
Shane
S
Waugh
Mark G
MG
Wiedemann
Claudia
C
Evangelou
Stylianos
S
Loesch
Andrzej
A
Sihra
Talvinder S
TS
King
Rosalind
R
Warner
Thomas T
TT
Hsuan
J Justin
JJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001774:Blood Chemical Analysis; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009410:Nerve Degeneration / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology* / Q000473:pathology
D015778:Minor Histocompatibility Antigens; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase