Gain-of-function Mutations in Protein Kinase C Alpha (PKC Alpha) May Promote Synaptic Defects in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-beta (A beta) accumulation in the brain. Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA, the gene that encodes protein kinase Ca (PKC alpha), in five of the families. All three variants linked with LOAD displayed increased catalytic activity relative to wild-type PKC alpha as assessed in live-cell imaging experiments using a genetically encoded PKC activity reporter. Deleting PRKCA in mice or adding PKC antagonists to mouse hippocampal slices infected with a virus expressing the A beta precursor CT100 revealed that PKC alpha was required for the reduced synaptic activity caused by A beta. InPRKCA-/- neurons expressing CT100, introduction of PKC alpha, but not PKC alpha lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKC alpha to the synapse is required for itsmediation of the effects of A beta. Thus, enhanced PKC alpha activity may contribute to AD, possibly bymediating the actions of A beta on synapses. In contrast, reduced PKC alpha activity is implicated in cancer. Hence, these findings reinforce the importance ofmaintaining a careful balance in the activity of this enzyme.