The four mammalian
phosphatidylinositol 4-kinases, together with the PI(4,5)
P(2) depleting 5-phosphatases of the
oculocerebrorenal syndrome of Lowe and
synaptojanin families, modulate neuronal pools of PI4P
lipid and regulate intracellular membrane trafficking in the endocytic and secretory pathways. Dysfunctions in these
enzymes have been associated with a broad spectrum of disorders including
schizophrenia,
bipolar disorder,
Lowe syndrome, age-related neurodegeneration,
Alzheimer's disease and
Down syndrome. Recent work has shown that reduced expression of individual
phosphatidylinositol 4-kinase isozymes is associated with impaired survival of specific neuronal populations within the CNS. Furthermore, alterations to the concentrations of different
phosphoinositide lipid species in the brain and, in particular, the ratio of PI4P to PI(4,5)
P(2) can have deleterious effects on
clathrin-dependent membrane trafficking both in the Golgi-endosomal pathway and at the plasma membrane. In this article, we focus on the cell biology, biochemistry and neuronal functions of the
phosphatidylinositol 4-kinases and their emerging roles in psychiatric and neurological pathologies.