Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease

Stephanie I. Alfonso, Julia A. Callender, Basavaraj Hooli, Corina E. Antal, Kristina Mullin, Mathew A. Sherman, Sylvain E. Lesné, Michael Leitges, Alexandra C. Newton, Rudolph E. Tanzi, Roberto Malinow

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

Original languageEnglish (US)
Article numberra47
JournalScience signaling
Issue number427
StatePublished - May 10 2016

Bibliographical note

Funding Information:
Funding: This work was supported by NIH GM43154 (A.C.N.), NIH MH060009 (R.E.T.), NIH AG032132 (R.M.), GM007752 (C.E.A.), DGE1144086 (C.E.A.), and Cure Alzheimer's Fund (R.E.T., A.C.N., and R.M.).


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