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.

journal_name

Sci Signal

journal_title

Science signaling

authors

Alfonso SI,Callender JA,Hooli B,Antal CE,Mullin K,Sherman MA,Lesné SE,Leitges M,Newton AC,Tanzi RE,Malinow R

doi

10.1126/scisignal.aaf6209

subject

Has Abstract

pub_date

2016-05-10 00:00:00

pages

ra47

issue

427

eissn

1945-0877

issn

1937-9145

pii

9/427/ra47

journal_volume

9

pub_type

杂志文章
  • Acetylation of Ets-1 is the key to chromatin remodeling for miR-192 expression.

    abstract::By regulating gene expression, microRNAs (miRNAs) play pivotal roles in physiological and pathological processes. However, the regulation of miRNAs is elusive. miR-192 is a key regulator of renal fibrosis and hypertrophy in diabetic nephropathy. Natarajan et al. showed that the miR-192 gene contains an upstream region...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004299

    authors: Dong Z

    更新日期:2013-06-04 00:00:00

  • Bacterial invaders drive CRC progression.

    abstract::The oral bacterium Fusobacterium nucleatum is often found in colorectal cancer (CRC). In the 21 July 2020 issue of Science Signaling, Casasanta et al show that CRC cell-resident F. nucleatum promotes cytokine secretion that may potentiate tumor growth and metastatic progression in patients. ...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.abc4218

    authors: Meyerson M

    更新日期:2020-08-11 00:00:00

  • An introduction to MATLAB.

    abstract::This two-part lecture introduces students to the scientific computing language MATLAB. Prior computer programming experience is not required. The lectures present basic concepts of computer programming logic that tend to cause difficulties for beginners in addition to concepts that relate specifically to the MATLAB la...

    journal_title:Science signaling

    pub_type:

    doi:10.1126/scisignal.2001984

    authors: Sobie EA

    更新日期:2011-09-13 00:00:00

  • Visualizing immune system complexity.

    abstract::The European Molecular Biology Organization (EMBO) meeting Visualizing Immune System Complexity, held in January 2009, covered multiple scales, from imaging single molecules to imaging whole animals. In addition to experimental details, there was an emphasis on modeling both for data analysis and as a predictive tool ...

    journal_title:Science signaling

    pub_type:

    doi:10.1126/scisignal.266mr4

    authors: Dustin ML

    更新日期:2009-04-14 00:00:00

  • Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice.

    abstract::The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient-sensitive protein kinase that is aberrantly activated in many human cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, which has been l...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002739

    authors: Menon S,Yecies JL,Zhang HH,Howell JJ,Nicholatos J,Harputlugil E,Bronson RT,Kwiatkowski DJ,Manning BD

    更新日期:2012-03-27 00:00:00

  • The second messenger c-di-AMP inhibits the osmolyte uptake system OpuC in Staphylococcus aureus.

    abstract::Staphylococcus aureus is an important opportunistic human pathogen that is highly resistant to osmotic stresses. To survive an increase in osmolarity, bacteria immediately take up potassium ions and small organic compounds known as compatible solutes. The second messenger cyclic diadenosine monophosphate (c-di-AMP) re...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aaf7279

    authors: Schuster CF,Bellows LE,Tosi T,Campeotto I,Corrigan RM,Freemont P,Gründling A

    更新日期:2016-08-16 00:00:00

  • Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5.

    abstract::Extracellular hyperosmolarity, or osmotic stress, generally caused by differences in salt and macromolecule concentrations across the plasma membrane, occurs in lymphoid organs and at inflammatory sites. The response of immune cells to osmotic stress is regulated by nuclear factor of activated T cells 5 (NFAT5), a tra...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2000081

    authors: Kino T,Takatori H,Manoli I,Wang Y,Tiulpakov A,Blackman MR,Su YA,Chrousos GP,DeCherney AH,Segars JH

    更新日期:2009-02-10 00:00:00

  • The basis for the distinct biological activities of vascular endothelial growth factor receptor-1 ligands.

    abstract::Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development through VEGF receptors (VEGFRs). The VEGFR immunoglobulin homology domain 2 (D2) is critical for ligand binding, and D3 provides additional interaction sites. VEGF-B and placenta growth factor (PlGF) bind to VEGFR-1 with high a...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2003905

    authors: Anisimov A,Leppänen VM,Tvorogov D,Zarkada G,Jeltsch M,Holopainen T,Kaijalainen S,Alitalo K

    更新日期:2013-07-02 00:00:00

  • Tumors block pain with CXCL12.

    abstract::The chemokine CXCL12 released from early stage pancreatic cancer recruits Schwann cells and suppresses pain signaling. ...

    journal_title:Science signaling

    pub_type: 评论,杂志文章

    doi:10.1126/scisignal.aam7233

    authors: Gough NR

    更新日期:2017-01-10 00:00:00

  • Systematic phosphorylation analysis of human mitotic protein complexes.

    abstract::Progression through mitosis depends on a large number of protein complexes that regulate the major structural and physiological changes necessary for faithful chromosome segregation. Most, if not all, of the mitotic processes are regulated by a set of mitotic protein kinases that control protein activity by phosphoryl...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2001993

    authors: Hegemann B,Hutchins JR,Hudecz O,Novatchkova M,Rameseder J,Sykora MM,Liu S,Mazanek M,Lénárt P,Hériché JK,Poser I,Kraut N,Hyman AA,Yaffe MB,Mechtler K,Peters JM

    更新日期:2011-11-08 00:00:00

  • The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria.

    abstract::The detection of microbes and initiation of an innate immune response occur through pattern recognition receptors (PRRs), which are critical for the production of inflammatory cytokines and activation of the cellular microbicidal machinery. In particular, the production of reactive oxygen species (ROS) by the NADPH ox...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aac6250

    authors: Billings EA,Lee CS,Owen KA,D'Souza RS,Ravichandran KS,Casanova JE

    更新日期:2016-02-02 00:00:00

  • Activation of CaMKIV by soluble amyloid-β1-42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis.

    abstract::The prefibrillar form of soluble amyloid-β (sAβ1-42) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sAβ1-42 led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aam8661

    authors: Park D,Na M,Kim JA,Lee U,Cho E,Jang M,Chang S

    更新日期:2017-07-11 00:00:00

  • Comment on "load-induced modulation of signal transduction networks": reconciling ultrasensitivity with bifunctionality?

    abstract::Jiang et al. (Research Article, 11 October 2011, DOI: 10.1126/scisignal.2002152) used a combined experimental and computational modeling approach to study the dynamic response behavior of covalent modification cycles in the presence of downstream targets ("loads"). Despite remarkable agreement between experiments and ...

    journal_title:Science signaling

    pub_type: 评论,信件

    doi:10.1126/scisignal.2002699

    authors: Straube R

    更新日期:2012-01-03 00:00:00

  • Focus issue: uncovering the mechanisms of neurological disease.

    abstract::This week, Science Signaling highlights research that uses computational and cell biology approaches to uncover the molecular mechanisms underlying diseases of the central nervous system. In particular, research featured explores the neuronal response to stress due to excess excitatory stimuli, multiple roles for pres...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.2004456

    authors: Ferrarelli LK,Gough NR

    更新日期:2013-07-09 00:00:00

  • Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation.

    abstract::The role of the mitochondrial Ca2+ uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output),...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aav1439

    authors: Koval OM,Nguyen EK,Santhana V,Fidler TP,Sebag SC,Rasmussen TP,Mittauer DJ,Strack S,Goswami PC,Abel ED,Grumbach IM

    更新日期:2019-04-30 00:00:00

  • ER stress in pancreatic beta cells: the thin red line between adaptation and failure.

    abstract::Secretory cells, such as pancreatic beta cells, face the challenge of increasing protein synthesis severalfold during acute or chronic stimulation. This poses a burden on the endoplasmic reticulum (ER), the organelle where proinsulin synthesis and folding takes place. Thus, beta cells use various adaptive mechanisms t...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.3110pe7

    authors: Eizirik DL,Cnop M

    更新日期:2010-02-23 00:00:00

  • Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6.

    abstract::Dickkopf1 (DKK1) was originally identified as an antagonist of Wnt signaling that binds to and induces the clathrin-mediated endocytosis of the Wnt coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). DKK1 also binds to cytoskeleton-associated protein 4 (CKAP4), which was originally identifi...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aat9519

    authors: Sada R,Kimura H,Fukata Y,Fukata M,Yamamoto H,Kikuchi A

    更新日期:2019-11-19 00:00:00

  • Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential.

    abstract::The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gαq/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gαq/11-coupled G protein-coupled receptors (GPCRs) to control downstream events, such as cell motility an...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aav2449

    authors: Bandekar SJ,Arang N,Tully ES,Tang BA,Barton BL,Li S,Gutkind JS,Tesmer JJG

    更新日期:2019-02-19 00:00:00

  • Aβ oligomers induce pathophysiological mGluR5 signaling in Alzheimer's disease model mice in a sex-selective manner.

    abstract::The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.abd2494

    authors: Abd-Elrahman KS,Albaker A,de Souza JM,Ribeiro FM,Schlossmacher MG,Tiberi M,Hamilton A,Ferguson SSG

    更新日期:2020-12-15 00:00:00

  • Target acquired: Selective autophagy in cardiometabolic disease.

    abstract::The accumulation of damaged or excess proteins and organelles is a defining feature of metabolic disease in nearly every tissue. Thus, a central challenge in maintaining metabolic homeostasis is the identification, sequestration, and degradation of these cellular components, including protein aggregates, mitochondria,...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.aag2298

    authors: Evans TD,Sergin I,Zhang X,Razani B

    更新日期:2017-02-28 00:00:00

  • Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis.

    abstract::Like phosphorylation, the addition of O-linked beta-N-acetylglucosamine (O-GlcNAcylation) is a ubiquitous, reversible process that modifies serine and threonine residues on nuclear and cytoplasmic proteins. Overexpression of the enzyme that adds O-GlcNAc to target proteins, O-GlcNAc transferase (OGT), perturbs cytokin...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2000526

    authors: Wang Z,Udeshi ND,Slawson C,Compton PD,Sakabe K,Cheung WD,Shabanowitz J,Hunt DF,Hart GW

    更新日期:2010-01-12 00:00:00

  • Single amino acid substitutions confer the antiviral activity of the TRAF3 adaptor protein onto TRAF5.

    abstract::The TRAF [tumor necrosis factor receptor-associated factor] family of cytoplasmic adaptor proteins link cell-surface receptors to intracellular signaling pathways that regulate innate and adaptive immune responses. In response to activation of RIG-I (retinoic acid-inducible gene I), a component of a pattern recognitio...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2003152

    authors: Zhang P,Reichardt A,Liang H,Aliyari R,Cheng D,Wang Y,Xu F,Cheng G,Liu Y

    更新日期:2012-11-13 00:00:00

  • Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs.

    abstract::MKK4 (mitogen-activated protein kinase kinase 4) is a pivotal upstream activator of c-Jun N-terminal kinase and p38. Here, we report that the abundance of MKK4 increases in senescent human diploid fibroblasts through enhanced translation. We identified four microRNAs (miR-15b, miR-24, miR-25, and miR-141) that target ...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2000442

    authors: Marasa BS,Srikantan S,Masuda K,Abdelmohsen K,Kuwano Y,Yang X,Martindale JL,Rinker-Schaeffer CW,Gorospe M

    更新日期:2009-10-27 00:00:00

  • ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.

    abstract::ONC201 (also called TIC10) is a small molecule that inactivates the cell proliferation- and cell survival-promoting kinases Akt and ERK and induces cell death through the proapoptotic protein TRAIL. ONC201 is currently in early-phase clinical testing for various malignancies. We found through gene expression and prote...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aac4374

    authors: Kline CL,Van den Heuvel AP,Allen JE,Prabhu VV,Dicker DT,El-Deiry WS

    更新日期:2016-02-16 00:00:00

  • TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α.

    abstract::Transforming growth factor-β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aal4186

    authors: Hamidi A,Song J,Thakur N,Itoh S,Marcusson A,Bergh A,Heldin CH,Landström M

    更新日期:2017-07-04 00:00:00

  • The cytoplasmic tail of MUC1: a very busy place.

    abstract::The role of mucin 1 (MUC1) in protecting epithelia from microbial infection, enzymatic digestion, and other irritants has been appreciated for some time. In addition, MUC1 serves as a barrier to embryo implantation. MUC1 is highly abundant in many tumors in which its role in barrier function may serve to protect cells...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.127pe35

    authors: Carson DD

    更新日期:2008-07-08 00:00:00

  • miR-221/222 targeting of trichorhinophalangeal 1 (TRPS1) promotes epithelial-to-mesenchymal transition in breast cancer.

    abstract::Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expr...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2002258

    authors: Stinson S,Lackner MR,Adai AT,Yu N,Kim HJ,O'Brien C,Spoerke J,Jhunjhunwala S,Boyd Z,Januario T,Newman RJ,Yue P,Bourgon R,Modrusan Z,Stern HM,Warming S,de Sauvage FJ,Amler L,Yeh RF,Dornan D

    更新日期:2011-08-09 00:00:00

  • Network-level effects of kinase inhibitors modulate TNF-α-induced apoptosis in the intestinal epithelium.

    abstract::Individual signaling pathways operate in the context of the broader signaling network. Thus, the response of a cell to signals from the environment is affected by the state of the signaling network, such as the clinically relevant example of whether some components in the network are inhibited. The cytokine tumor necr...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.aac7235

    authors: Gierut JJ,Wood LB,Lau KS,Lin YJ,Genetti C,Samatar AA,Lauffenburger DA,Haigis KM

    更新日期:2015-12-15 00:00:00

  • The chemokine CXCL12 generates costimulatory signals in T cells to enhance phosphorylation and clustering of the adaptor protein SLP-76.

    abstract::The CXC chemokine CXCL12 mediates the chemoattraction of T cells and enhances the stimulation of T cells through the T cell receptor (TCR). The adaptor SLP-76 [Src homology 2 (SH2) domain-containing leukocyte protein of 76 kD] has two key tyrosine residues, Tyr(113) and Tyr(128), that mediate signaling downstream of t...

    journal_title:Science signaling

    pub_type: 杂志文章

    doi:10.1126/scisignal.2004018

    authors: Smith X,Schneider H,Köhler K,Liu H,Lu Y,Rudd CE

    更新日期:2013-07-30 00:00:00

  • The HIF-1 alpha-C/EBP alpha axis.

    abstract::The hypoxia inducible factors (HIFs) and CCAAT/enhancer binding protein alpha (C/EBP alpha) are transcription factors that mediate adaptive responses to hypoxia and control aspects of energy metabolism, respectively. New evidence suggests that when HIF-1 alpha and C/EBP alpha interact, they bring about reciprocal func...

    journal_title:Science signaling

    pub_type: 杂志文章,评审

    doi:10.1126/scisignal.143jc2

    authors: Janardhan HP

    更新日期:2008-10-28 00:00:00