Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain

Abstract

Phosphatidylinositol-4,5-bisphosphate (PI-4,5-P 2 ) is critical for synaptic vesicle docking and fusion and generation of the second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. PI-4,5-P 2 can be generated by two families of kinases: type 1 phosphatidylinositol-4-phosphate 5kinases, encoded by PIP5K1A, PIP5K1B and PIP5K1C, and type 2 phosphatidylinositol-5phosphate 4-kinases, encoded by PIP4K2A, PIP4K2B, and PIP4K2C. While the roles of the type 1 enzymes in brain function have been extensively studied, the roles of the type 2 enzymes are poorly understood. Using selective antibodies validated by genetic deletion of pip4k2a or pip4k2b in mouse brain, we characterized the location of the enzymes, PI5P4Kα and PI5P4Kß, encoded by these genes. In mice, we demonstrate that PI5P4Kα is expressed in adulthood, whereas PI5P4Kß is expressed early in development. PI5P4Kα localizes to white matter tracts, especially the corpus callosum, and at a low level in neurons, while PI5P4Kß is expressed in neuronal populations, especially hippocampus and cortex. Dual labeling studies demonstrate that PI5P4Kα co-localizes with the oligodendrocyte marker, Olig2, whereas PI5P4Kß co-localizes with the neuronal marker, NeuN. Immunohistochemical subcellular distribution studies demonstrate that PI5P4Kα and PI5P4Kß are expressed in the early endosome system. Ultrastructural analysis demonstrates that both kinases are contained in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission. Immunohistochemical analysis of macaque and human brain tissue demonstrate a conserved pattern for PI5P4Kα and PI5P4Kß. These results highlight the diverse cell-autonomous expression of PI5P4Kα and PI5P4Kß and support further exploration into their role in synaptic function in the brain.

A human tau seeded neuronal cell model recapitulates molecular responses associated with Alzheimer’s disease

“…Pip4k2b in the mouse brain is expressed developmentally in neuronal populations, especially hippocampus and cortex, where it is co-localised with the marker NeuN. It is present in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission 63 .…”

Beyond PI3Ks: targeting phosphoinositide kinases in disease

“…In addition, genome-wide association studies associate polymorphisms of PIP4K2A with elevated risk of schizophrenia [123][124][125] . Although no causative relationship for the correlation has been found, the PI5P4Ks are enriched in neural tissues and are hypothesized to affect synaptic function 126 .…”