Protein kinase C delta (PKCδ), a calcium-independent novel PKC isoform, is increasingly recognized as a compartmentalized regulator of stress signaling in the central nervous system. Through tyrosine phosphorylation, subcellular translocation, regulation of its expression, and caspase-3-dependent proteolytic activation, PKCδ can convert transient adaptive responses into sustained oxidative, mitochondrial, inflammatory, and nuclear apoptotic signaling. This review evaluates PKCδ across Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and ischemic stroke, emphasizing disease- and cell type-specific mechanisms rather than a uniformly pathogenic role. In PD, PKCδ most consistently amplifies toxin- and α-synuclein-associated dopaminergic injury and glial inflammation, although human evidence remains limited. In AD, PKCδ may link amyloidogenic processing of amyloid precursor protein (APP), amyloid-beta peptide (Aβ)-induced neuronal stress/cell cycle reentry, and glial neuroinflammation in a context-dependent feed-forward circuit. In HD, PKCδ signaling may shift from early compensatory downregulation to stress-induced apoptotic reactivation. In ischemic stroke, the strongest evidence implicates PKCδ in reperfusion-associated oxidative and inflammatory injury, particularly through neutrophil and translocation-dependent mechanisms. Future therapeutic development will require isoform-selective, compartment-specific, and cell type-resolved PKCδ modulation.
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