title: 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.
authors.affiliation: Department of Neurosciences and Division of Biology, Section of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Stephanie I
authors.initials: SI
authors.lastname: Alfonso
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA. Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Callender
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Basavaraj
authors.initials: B
authors.lastname: Hooli
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA. Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Corina E
authors.initials: CE
authors.lastname: Antal
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Mullin
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Sherman
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: Sylvain E
authors.initials: SE
authors.lastname: Lesné
authors.affiliation: Biotechnology Centre of Oslo, University of Oslo, Oslo 0317, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA. anewton@ucsd.edu tanzi@helix.mgh.harvard.edu rmalinow@ucsd.edu.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. anewton@ucsd.edu tanzi@helix.mgh.harvard.edu rmalinow@ucsd.edu.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: Department of Neurosciences and Division of Biology, Section of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA. anewton@ucsd.edu tanzi@helix.mgh.harvard.edu rmalinow@ucsd.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Malinow
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005192:Family Health; D016678:Genome; D015894:Genome, Human; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D000072417:Protein Domains; D051571:Protein Kinase C-alpha / Q000235:genetics*; D013569:Synapses / Q000473:pathology*
chemical_list: C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha