Protein phosphatase 3 catalytic subunit alpha

Protein phosphatase 3 catalytic subunit alpha (PPP3CA) is a calcium-dependent, calmodulin-stimulated serine/threonine phosphatase essential for transducing intracellular calcium signals (UniProt: Q08209). It dephosphorylates numerous substrates including SSH1, DNM1L, NFATC1, and transcription factors, thereby regulating processes from mitochondrial dynamics to gene expression. The enzyme recognizes substrates bearing PxIxIT or LxVP motifs and plays roles in neuronal synaptic function, including homosynaptic depotentiation in the hippocampus.

PPP3CA is widely expressed and functions in diverse tissues including kidney, salivary glands, bone, immune cells, and skeletal muscle (UniProt: Q08209). Mutations in PPP3CA are associated with infantile or early childhood epileptic encephalopathy (IECEE1, MIM 617711) and arthrogryposis with cleft palate and craniosynostosis (ACCIID, MIM 618265), highlighting its critical role in neurodevelopment and embryonic patterning.

In Alzheimer's Disease, PPP3CA is significantly downregulated in post-mortem human AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.45 (Chaparral AD proteomics). This reduction may impair calcium-dependent signaling and NFAT-mediated transcription relevant to neuroinflammation and neuronal survival pathways implicated in AD pathophysiology.