Gain-of-function mutations in protein kinase C? (PKC?) may promote synaptic defects in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-? (A?) 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 C? (PKC?), in five of the families. All three variants linked with LOAD displayed increased catalytic activity relative to wild-type PKC? 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? precursor CT100 revealed that PKC? was required for the reduced synaptic activity caused by A?. In PRKCA(-/-)?neurons expressing CT100, introduction of PKC?, but not PKC? lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKC? to the synapse is required for its mediation of the effects of A?. Thus, enhanced PKC? activity may contribute to AD, possibly by mediating the actions of A? on synapses. In contrast, reduced PKC? activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme.

SUBMITTER: Alfonso SI 

PROVIDER: S-EPMC5154619 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature