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

Abstract

Alzheimer’s disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-β (Aβ) 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. In PRKCA−/− 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 its mediation of the effects of Aβ. Thus, enhanced PKCα activity may contribute to AD, possibly by mediating the actions of Aβ on synapses. In contrast, reduced PKCα activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme.

Conventional protein kinase C in the brain: 40 years later

“…Genome-wide sequencing of Alzheimer families resulted in the recent identification of three highly penetrant PKCα mutations that co-segregated with AD in human patients [12]. All three mutations enhanced PKCα signaling output, supporting the hypothesis that enhanced PKCα signaling may contribute to AD pathology.…”

“…One possible mechanism for the downstream effects of PKC could be by controlling receptor function: exposure of synapses to Aβ peptide in vitro causes a decrease in GluA2-containing AMPA receptors facing the synapse, and GluA2 mutants incapable of regulating endocytosis are insensitive to Aβ-induced synaptic depression [99]. PKCα and its scaffold PICK1 play a critical role in AMPAR internalization, and both PICK1 and PKCα are required for Aβ-mediated synaptic depression [12,97]. Thus, a reasonable hypothesis is that PKCα promotes neurodegeneration by removing AMPA receptors from synapses.…”

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

“…The phosphorylation of the GluA2 or GluA3 c-tail by protein kinase Cα (PKCα) permits PICK1 binding, leading to AMPAR endocytosis (35,36). Notably, PICK1 and PKCα are necessary for Aβ-mediated synaptic depression to take place (37,38). The PICK1-dependent removal of AMPARs from the surface by Aβ was shown to be more prominent for GluA2 than for GluA1 (37), suggesting that Aβ oligomers particularly trigger the endocytosis of GluA2/3s.…”

A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells

“…DAG binding domain mutations that reduce PKC␥ catalytic activity cause spinocerebellar ataxia type 14, an autosomal dominant neurodegenerative disease (16,17). In an Alzheimer's disease model, toxic A␤ amyloid protein disrupts synaptic structure and functions in hippocampus by promoting PKC␣ activation and concomitant glutamate receptor phosphorylation and endocytosis (18,19). Supraphysiological kinase activity of PKC␣ variants is tightly linked to dementia in a group of families afflicted with high incidences of severe, late-onset Alzheimer's disease (18).…”

“…In an Alzheimer's disease model, toxic A␤ amyloid protein disrupts synaptic structure and functions in hippocampus by promoting PKC␣ activation and concomitant glutamate receptor phosphorylation and endocytosis (18,19). Supraphysiological kinase activity of PKC␣ variants is tightly linked to dementia in a group of families afflicted with high incidences of severe, late-onset Alzheimer's disease (18). PKC␤-deficient mice are impaired in amygdala-dependent associative learning (20).…”