Phosphatidylinositol 4-kinase alpha

PI4KA (phosphatidylinositol 4-kinase alpha) catalyzes the first committed step in inositol-1,4,5-trisphosphate production, a crucial second messenger in cellular signaling (UniProt: P42356). The protein operates in phosphatidylinositol metabolism, which is fundamental to diverse cellular processes including membrane trafficking and signal transduction. Beyond its normal physiological role, PI4KA mutations are associated with several severe monogenic disorders affecting the nervous system and gastrointestinal tract, including neurodevelopmental disorder with spasticity and hypomyelinating leukodystrophy (NEDSPLB, MIM 616531) and spastic paraplegia 84 (SPG84, MIM 619621) (UniProt: P42356).

In Alzheimer's Disease, PI4KA is significantly downregulated in post-mortem human AD brain tissue compared to age-matched controls (Chaparral AD proteomics). Across the subcellular fractions examined in TMT-labeled proteomics analysis, the protein showed a mean log2-fold change of −0.73, indicating reduced abundance in the diseased brain. This downregulation may contribute to impaired phosphoinositide signaling in AD pathology, potentially affecting membrane dynamics and cellular responses critical to neuronal function. The biological significance of PI4KA reduction in AD progression warrants further investigation.