Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease.

Abstract:

:The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with mutations in the Notch 3 receptor. CADASIL pathology is characterized by vascular smooth muscle cell degeneration and accumulation of diagnostic granular osmiophilic material (GOM) in vessels. The functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease and GOM accumulation remain enigmatic. To gain insight into how Notch 3 function is linked to CADASIL pathophysiology, we studied two phenotypically distinct mutations, C455R and R1031C, respectively associated with early and late onset of stroke, by using hemodynamic analyses in transgenic mouse models, receptor activity assays in cell culture, and proteomic examination of postmortem human tissue. We demonstrate that the C455R and R1031C mutations define different hypomorphic activity states of Notch 3, a property linked to ischemic stroke susceptibility in mouse models we generated. Importantly, these mice develop osmiophilic deposits and other age-dependent phenotypes that parallel remarkably the human condition. Proteomic analysis of human brain vessels, carrying the same CADASIL mutations, identified clusterin and collagen 18 α1/endostatin as GOM components. Our findings link loss of Notch signaling with ischemic cerebral small-vessel disease, a prevalent human condition. We determine that CADASIL pathophysiology is associated with hypomorphic Notch 3 function in vascular smooth muscle cells and implicate the accumulation of clusterin and collagen 18 α1/endostatin in brain vessel pathology.

authors

Arboleda-Velasquez JF,Manent J,Lee JH,Tikka S,Ospina C,Vanderburg CR,Frosch MP,Rodríguez-Falcón M,Villen J,Gygi S,Lopera F,Kalimo H,Moskowitz MA,Ayata C,Louvi A,Artavanis-Tsakonas S

doi

10.1073/pnas.1101964108

subject

Has Abstract

pub_date

2011-05-24 00:00:00

pages

E128-35

issue

21

eissn

0027-8424

issn

1091-6490

pii

1101964108

journal_volume

108

pub_type

杂志文章
  • Simian virus 40 minichromosomes as targets for retroviral integration in vivo.

    abstract::We present a method for studying multiple retroviral integration events into a small DNA target in vivo. Episomal simian virus 40 (SV40) genomes established by infection of CV-1 cells served as integration targets during subsequent infection with murine leukemia virus (MLV). Using a PCR-based assay for the abundance a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.19.9237

    authors: Pryciak PM,Müller HP,Varmus HE

    更新日期:1992-10-01 00:00:00

  • LsrF, a coenzyme A-dependent thiolase, catalyzes the terminal step in processing the quorum sensing signal autoinducer-2.

    abstract::The quorum sensing signal autoinducer-2 (AI-2) regulates important bacterial behaviors, including biofilm formation and the production of virulence factors. Some bacteria, such as Escherichia coli, can quench the AI-2 signal produced by a variety of species present in the environment, and thus can influence AI-2-depen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1408691111

    authors: Marques JC,Oh IK,Ly DC,Lamosa P,Ventura MR,Miller ST,Xavier KB

    更新日期:2014-09-30 00:00:00

  • Insulin activates a 70-kDa S6 kinase through serine/threonine-specific phosphorylation of the enzyme polypeptide.

    abstract::The dominant insulin-stimulated ribosomal protein S6 kinase activity was purified to near homogeneity from insulin-treated 32P-labeled rat H4 hepatoma cells and found to copurify with a 70-kDa 32P-labeled polypeptide. The dominant S6 kinase purified from livers of cycloheximide-treated rats is also a 70-kDa polypeptid...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.20.7944

    authors: Price DJ,Gunsalus JR,Avruch J

    更新日期:1990-10-01 00:00:00

  • The subtilisin E gene of Bacillus subtilis is transcribed from a sigma 37 promoter in vivo.

    abstract::A cloned Bacillus subtilis gene (sprE) expressed only during the stationary growth phase is shown to encode the subtilisin E protease, an enzyme associated with sporulation. We have determined the DNA sequence of the sprE promoter region and the promoter-proximal half of the structural gene. The sprE gene codes for a ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.4.1184

    authors: Wong SL,Price CW,Goldfarb DS,Doi RH

    更新日期:1984-02-01 00:00:00

  • Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart.

    abstract::Identification of genomic regions that control tissue-specific gene expression is currently problematic. ChIP and high-throughput sequencing (ChIP-seq) of enhancer-associated proteins such as p300 identifies some but not all enhancers active in a tissue. Here we show that co-occupancy of a chromatin region by multiple...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1016959108

    authors: He A,Kong SW,Ma Q,Pu WT

    更新日期:2011-04-05 00:00:00

  • Efficient transduction of neural cells in vitro and in vivo by a baculovirus-derived vector.

    abstract::Gene delivery to the central nervous system is central to the development of gene therapy for neurological diseases. We developed a baculovirus-derived vector, the Bac-CMV-GFP vector, containing a reporter gene encoding for the green fluorescent protein (GFP) under the control of the cytomegalovirus (CMV) promoter. Tw...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.260472897

    authors: Sarkis C,Serguera C,Petres S,Buchet D,Ridet JL,Edelman L,Mallet J

    更新日期:2000-12-19 00:00:00

  • An antimicrobial peptide essential for bacterial survival in the nitrogen-fixing symbiosis.

    abstract::In the nitrogen-fixing symbiosis between legume hosts and rhizobia, the bacteria are engulfed by a plant cell membrane to become intracellular organelles. In the model legume Medicago truncatula, internalization and differentiation of Sinorhizobium (also known as Ensifer) meliloti is a prerequisite for nitrogen fixati...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1500123112

    authors: Kim M,Chen Y,Xi J,Waters C,Chen R,Wang D

    更新日期:2015-12-08 00:00:00

  • Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria.

    abstract::Selective autophagy of damaged mitochondria requires autophagy receptors optineurin (OPTN), NDP52 (CALCOCO2), TAX1BP1, and p62 (SQSTM1) linking ubiquitinated cargo to autophagic membranes. By using quantitative proteomics, we show that Tank-binding kinase 1 (TBK1) phosphorylates all four receptors on several autophagy...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1523926113

    authors: Richter B,Sliter DA,Herhaus L,Stolz A,Wang C,Beli P,Zaffagnini G,Wild P,Martens S,Wagner SA,Youle RJ,Dikic I

    更新日期:2016-04-12 00:00:00

  • The three-dimensional structure of an H-2Ld-peptide complex explains the unique interaction of Ld with beta-2 microglobulin and peptide.

    abstract::Solution at 2.5-A resolution of the three-dimensional structure of H-2Ld with a single nine-residue peptide provides a structural basis for understanding its unique interaction with beta-2 microglobulin (beta2m) and peptide. Consistent with the biological data that show an unusually weak association of Ld with beta2m,...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.13.6880

    authors: Balendiran GK,Solheim JC,Young AC,Hansen TH,Nathenson SG,Sacchettini JC

    更新日期:1997-06-24 00:00:00

  • A humanized antibody that binds to the interleukin 2 receptor.

    abstract::The anti-Tac monoclonal antibody is known to bind to the p55 chain of the human interleukin 2 receptor and to inhibit proliferation of T cells by blocking interleukin 2 binding. However, use of anti-Tac as an immunosuppressant drug would be impaired by the human immune response against this murine antibody. We have th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.24.10029

    authors: Queen C,Schneider WP,Selick HE,Payne PW,Landolfi NF,Duncan JF,Avdalovic NM,Levitt M,Junghans RP,Waldmann TA

    更新日期:1989-12-01 00:00:00

  • Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.

    abstract::Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼ 5% of t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1419533112

    authors: Xu M,Kobets A,Du JC,Lennington J,Li L,Banasr M,Duman RS,Vaccarino FM,DiLeone RJ,Pittenger C

    更新日期:2015-01-20 00:00:00

  • Dynamic antibody responses to the Mycobacterium tuberculosis proteome.

    abstract::Considerable effort has been directed toward controlling tuberculosis, which kills almost two million people yearly. High on the research agenda is the discovery of biomarkers of active tuberculosis (TB) for diagnosis and for monitoring treatment outcome. Rational biomarker discovery requires understanding host-pathog...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1009080107

    authors: Kunnath-Velayudhan S,Salamon H,Wang HY,Davidow AL,Molina DM,Huynh VT,Cirillo DM,Michel G,Talbot EA,Perkins MD,Felgner PL,Liang X,Gennaro ML

    更新日期:2010-08-17 00:00:00

  • Specific binding of leukotriene C4 to ileal segments and subcellular fractions of ileal smooth muscle cells.

    abstract::A specific high-affinity receptor for leukotriene C4 (LTC4) has been identified on segments of longitudinal smooth muscle from guinea pig ileum, in disrupted cells obtained from the ileal segments, and in subcellular fractions enriched for mitochondrial membranes and plasma membranes, respectively. Specific [3H]LTC4 b...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.14.4529

    authors: Krilis S,Lewis RA,Corey EJ,Austen KF

    更新日期:1984-07-01 00:00:00

  • Arc regulates spine morphology and maintains network stability in vivo.

    abstract::Long-term memory relies on modulation of synaptic connections in response to experience. This plasticity involves trafficking of AMPA receptors (AMPAR) and alteration of spine morphology. Arc, a gene induced by synaptic activity, mediates the endocytosis of AMPA receptors and is required for both long-term and homeost...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1006546107

    authors: Peebles CL,Yoo J,Thwin MT,Palop JJ,Noebels JL,Finkbeiner S

    更新日期:2010-10-19 00:00:00

  • Spatially clustered neuronal assemblies comprise the microstructure of synchrony in chronically epileptic networks.

    abstract::Epilepsy is characterized by recurrent synchronizations of neuronal activity, which are both a cardinal clinical symptom and a debilitating phenomenon. Although the temporal dynamics of epileptiform synchronizations are well described at the macroscopic level using electrophysiological approaches, less is known about ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1216958110

    authors: Feldt Muldoon S,Soltesz I,Cossart R

    更新日期:2013-02-26 00:00:00

  • Mating signal and DNA penetration deficiency in conjugation between male Escherichia coli and minicells.

    abstract::Strain OU122, a dnaB mutant of HfrH which stops vegetative DNA synthesis immediately when the temperature is shifted to 43 degrees, was mated at 43 degrees with minicells with and without 1 mM Zn2+. Synthesis of DNA was detected in the mating mixture containing minicells derived from either Fchi925 or F+chi115 cells, ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.72.9.3721

    authors: Ou JT

    更新日期:1975-09-01 00:00:00

  • Expression of murine renin genes in subcutaneous connective tissue.

    abstract::A renin promoter-large tumor antigen (T antigen) fusion gene was constructed to provide a reporter function for renin expression in transgenic mice. These transgenic mice gave rise to tumors in subcutaneous soft tissue, which was attributed to transgene expression at this site. An immunohistochemical analysis of trans...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.20.7993

    authors: Sigmund CD,Jones CA,Mullins JJ,Kim U,Gross KW

    更新日期:1990-10-01 00:00:00

  • Chromosome disentanglement driven via optimal compaction of loop-extruded brush structures.

    abstract::Eukaryote cell division features a chromosome compaction-decompaction cycle that is synchronized with their physical and topological segregation. It has been proposed that lengthwise compaction of chromatin into mitotic chromosomes via loop extrusion underlies the compaction-segregation/resolution process. We analyze ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1906355116

    authors: Brahmachari S,Marko JF

    更新日期:2019-12-10 00:00:00

  • Reconciling anthropogenic climate change with observed temperature 1998-2008.

    abstract::Given the widely noted increase in the warming effects of rising greenhouse gas concentrations, it has been unclear why global surface temperatures did not rise between 1998 and 2008. We find that this hiatus in warming coincides with a period of little increase in the sum of anthropogenic and natural forcings. Declin...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 历史文章,杂志文章

    doi:10.1073/pnas.1102467108

    authors: Kaufmann RK,Kauppi H,Mann ML,Stock JH

    更新日期:2011-07-19 00:00:00

  • Addition of a photocrosslinking amino acid to the genetic code of Escherichiacoli.

    abstract::Benzophenones are among the most useful photocrosslinking agents in biology. We have evolved an orthogonal aminoacyl-tRNA synthetase/tRNA pair that makes possible the in vivo incorporation of p-benzoyl-l-phenylalanine into proteins in Escherichia coli in response to the amber codon, TAG. This unnatural amino acid was ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.172226299

    authors: Chin JW,Martin AB,King DS,Wang L,Schultz PG

    更新日期:2002-08-20 00:00:00

  • Importance of ocean salinity for climate and habitability.

    abstract::Modeling studies of terrestrial extrasolar planetary climates are now including the effects of ocean circulation due to a recognition of the importance of oceans for climate; indeed, the peak equator-pole ocean heat transport on Earth peaks at almost half that of the atmosphere. However, such studies have made the ass...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1522034113

    authors: Cullum J,Stevens DP,Joshi MM

    更新日期:2016-04-19 00:00:00

  • Endogenous sources of variation in language acquisition.

    abstract::A fundamental question in the study of human language acquisition centers around apportioning explanatory force between the experience of the learner and the core knowledge that allows learners to represent that experience. We provide a previously unidentified kind of data identifying children's contribution to langua...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1517094113

    authors: Han CH,Musolino J,Lidz J

    更新日期:2016-01-26 00:00:00

  • Copy number alteration burden predicts prostate cancer relapse.

    abstract::Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discov...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 临床试验,杂志文章

    doi:10.1073/pnas.1411446111

    authors: Hieronymus H,Schultz N,Gopalan A,Carver BS,Chang MT,Xiao Y,Heguy A,Huberman K,Bernstein M,Assel M,Murali R,Vickers A,Scardino PT,Sander C,Reuter V,Taylor BS,Sawyers CL

    更新日期:2014-07-29 00:00:00

  • A simple technique for generating probes for RNA in situ hybridization: an adjunct to genome mapping exemplified by the RAG-1/RAG-2 gene cluster.

    abstract::Two major problems have to be solved in studies of genes near breakpoints of chromosome abnormalities and in large-scale genomic mapping projects: (i) the identification of genes within the large amount on nontranscribed DNA and (ii) the determination of the tissues in which the identified genes are transcribed. In si...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.9.3927

    authors: Boehm T,Gonzalez-Sarmiento R,Kennedy M,Rabbitts TH

    更新日期:1991-05-01 00:00:00

  • Conformational plasticity of glycogenin and its maltosaccharide substrate during glycogen biogenesis.

    abstract::Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis. We have captured crystallographic snapshots of human glycogenin during its reaction cycle, revealing a dynamic conformational switch between ground an...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1113921108

    authors: Chaikuad A,Froese DS,Berridge G,von Delft F,Oppermann U,Yue WW

    更新日期:2011-12-27 00:00:00

  • Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates.

    abstract::The mutagenic effect of low linear energy transfer ionizing radiation is reduced for a given dose as the dose rate (DR) is reduced to a low level, a phenomenon known as the direct DR effect. Our reanalysis of published data shows that for both somatic and germ-line mutations there is an opposite, inverse DR effect, wi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.090099497

    authors: Vilenchik MM,Knudson AG Jr

    更新日期:2000-05-09 00:00:00

  • Moral consequences of becoming unemployed.

    abstract::We test the conjecture that becoming unemployed erodes the extent to which a person acknowledges earned entitlement. We use behavioral experiments to generate incentive-compatible measures of individuals' tendencies to acknowledge earned entitlement and incorporate these experiments in a two-stage study. In the first ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1521250113

    authors: Barr A,Miller L,Ubeda P

    更新日期:2016-04-26 00:00:00

  • The 289-amino acid E1A protein of adenovirus binds zinc in a region that is important for trans-activation.

    abstract::The E1A gene of adenovirus type 5 encodes two major proteins of 289 and 243 amino acid residues, which are identical except that the larger protein has an internal stretch of 46 amino acids required for efficient trans-activation of early viral promoters. This domain contains a consensus zinc finger motif (Cys-Xaa2-Cy...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.85.17.6450

    authors: Culp JS,Webster LC,Friedman DJ,Smith CL,Huang WJ,Wu FY,Rosenberg M,Ricciardi RP

    更新日期:1988-09-01 00:00:00

  • Metabolism of benzo[a]pyrene by human mammary epithelial cells: toxicity and DNA adduct formation.

    abstract::Pure cultures of human breast epithelial cells and of fibroblastic cells in early passage provided the opportunity to ask whether either cell type had the capability for metabolizing chemical carcinogens and, if so, was the fate of the metabolic products compatible with chemical carcinogens being a factor in the initi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.10.6251

    authors: Stampfer MR,Bartholomew JC,Smith HS,Bartley JC

    更新日期:1981-10-01 00:00:00

  • Desensitization of enucleated cells to hormones and role of cytoskeleton in control of normal hormonal response.

    abstract::Prostaglandin E1 and the beta-adrenergic hormone l-isoproterenol stimulated cyclic AMP formation in both nucleated and enucleated myeloid leukemic cells that could be induced to differentiate normally to mature cells by the macrophage- and granulocyte-inducing protein MGI (MGI+D+ cells). Enucleated as well as nucleate...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.8.4798

    authors: Simantov R,Shkolnik T,Sachs L

    更新日期:1980-08-01 00:00:00