Abstract:
:Alzheimer's disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.
journal_name
Proc Natl Acad Sci U S Aauthors
Fernandez-Funez P,Sanchez-Garcia J,de Mena L,Zhang Y,Levites Y,Khare S,Golde TE,Rincon-Limas DEdoi
10.1073/pnas.1608045113subject
Has Abstractpub_date
2016-08-30 00:00:00pages
E5212-21issue
35eissn
0027-8424issn
1091-6490pii
1608045113journal_volume
113pub_type
杂志文章abstract::Proopiomelanocortin (POMC), a major pituitary product, is also present in the adult mouse testis. We have shown previously that POMC mRNAs are most abundant in a subpopulation of Leydig cells associated with tubules in specific stages of the cycle of the seminiferous epithelium. In the present study, we examined the e...
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.84.6.1600
更新日期:1987-03-01 00:00:00
abstract::Marine Archaea are important players among microbial plankton and significantly contribute to biogeochemical cycles, but details regarding their community structure and long-term seasonal activity and dynamics remain largely unexplored. In this study, we monitored the interannual archaeal community composition of abun...
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.1216863110
更新日期:2013-04-09 00:00:00
abstract::Ancient societies are often used to illustrate the potential problems stemming from unsustainable land-use practices because the past seems rife with examples of sociopolitical "collapse" associated with the exhaustion of finite resources. Just as frequently, and typically in response to such presentations, archaeolog...
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.1409646111
更新日期:2014-08-12 00:00:00
abstract::Three-dimensional topological insulators (3D TIs) represent states of quantum matters in which surface states are protected by time-reversal symmetry and an inversion occurs between bulk conduction and valence bands. However, the bulk-band inversion, which is intimately tied to the topologically nontrivial nature of 3...
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.1613110114
更新日期:2017-01-31 00:00:00
abstract::The secreted nodulation-signaling protein NodO was purified from the supernatant of cultures of Rhizobium leguminosarum biovar viciae. The native protein has a M(r) of approximately 67,000, suggesting that it exists as a dimer since the DNA sequence predicts a M(r) of 30,002. Pure NodO protein had no protease, pectina...
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.91.21.9990
更新日期:1994-10-11 00:00:00
abstract::Inherited colorectal cancer syndromes in humans exhibit regional specificity for tumor formation. By using mice with germline mutations in the adenomatous polyposis coli gene (Apc) and/or DNA mismatch repair genes, we have analyzed the genetic control of tumor regionality in the mouse small intestine. In C57BL/6 mice ...
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.0403338101
更新日期:2004-06-29 00:00:00
abstract::We describe the use of the matrix eigenvalue decomposition (EVD) and pseudoinverse projection and a tensor higher-order EVD (HOEVD) in reconstructing the pathways that compose a cellular system from genome-scale nondirectional networks of correlations among the genes of the system. The EVD formulates a genes x genes n...
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.0509033102
更新日期:2005-12-06 00:00:00
abstract::Transgenic crops producing Bacillus thuringiensis (Bt) toxins kill some key insect pests and thus can reduce reliance on insecticides. Widespread planting of such Bt crops increased concerns that their usefulness would be cut short by rapid evolution of resistance to Bt toxins by pests. Pink bollworm (Pectinophora gos...
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.0507857102
更新日期:2005-10-25 00:00:00
abstract::Hypermutation in immunoglobulin genes produces a high frequency of substitutions of all four bases, which are likely generated by low-fidelity DNA polymerases. Indeed, humans deficient for DNA polymerase (pol) eta have decreased substitutions of A.T base pairs in variable and switch regions. To study the role of pol e...
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.0501852102
更新日期:2005-06-14 00:00:00
abstract::At high altitude (HA), carbohydrate (CHO) is thought to be the preferred fuel because of its higher yield of ATP per mole of O2. We used indirect calorimetry and D-[6-3H]glucose infusions to determine total CHO and circulatory glucose utilization during exercise in HA-acclimated and sea level (SL) rats. We hypothesize...
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.95.17.10288
更新日期:1998-08-18 00:00:00
abstract::We perform a generalized-ensemble simulation of a small peptide taking the interactions among all atoms into account. From this simulation we obtain thermodynamic quantities over a wide range of temperatures. In particular, we show that the folding of a small peptide is a multistage process associated with two charact...
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.94.20.10652
更新日期:1997-09-30 00:00:00
abstract::Phytochrome is the photoreceptor that controls red light-mediated morphogenesis in higher plants. It exists in two photointerconvertible forms, a red light-absorbing form, Pr, and a far-red light-absorbing form, Pfr. Because photoconversion of Pr to Pfr by a brief light pulse decreases the in vivo half-life of this ch...
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.84.2.359
更新日期:1987-01-01 00:00:00
abstract::Glucagon-like peptide 1 (GLP-1) is a hormone derived from the preproglucagon molecule and is secreted by intestinal L cells. It is the most potent stimulator of glucose-induced insulin secretion and also suppresses in vivo acid secretion by gastric glands. A cDNA for the GLP-1 receptor was isolated by transient expres...
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.89.18.8641
更新日期:1992-09-15 00:00:00
abstract::p53, the most commonly mutated gene in human tumors, is believed to play a crucial role in the prevention of cancer by protecting cells from mutation, a theory commonly known as the "Guardian of the Genome" hypothesis. There are two hypotheses as to how this can occur. In the first, p53 protects the genome by retardin...
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.2235595100
更新日期:2003-10-28 00:00:00
abstract::Interleukin 6 (IL-6) is a cytokine that acts on various cell types. Here we show that IL-6 mRNA is produced in vivo in two self-limiting physiologic angiogenic processes: (i) the formation of the vascular system accompanying development of ovarian follicles and (ii) the formation of a capillary network in the maternal...
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.87.8.3092
更新日期:1990-04-01 00:00:00
abstract::Ras CAAX (C = cysteine, A = aliphatic amino acid, and X = any amino acid) peptidomimetic inhibitors of farnesyl protein transferase suppress Ras-dependent cell transformation by preventing farnesylation of the Ras oncoprotein. These compounds are potential anticancer agents for tumors associated with Ras mutations. 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.92.24.10919
更新日期:1995-11-21 00:00:00
abstract::Cell type in Saccharomyces yeasts is regulated by two transposable blocks of DNA, the a and alpha cassettes. There are three loci where either cassette can exist. At the HML and HMR loci the cassettes are not expressed. The cassette at the MAT locus is expressed and controls the cell type. Changes of cell type involve...
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.77.5.2839
更新日期:1980-05-01 00:00:00
abstract::Five instances of association between distinctive stromatolites and blue-green algal nannofossils are recorded from a 100-m sequence of carbonate rocks about 1.6 x 10(9) years old, along the south side of Paradise Creek, northwestern Queensland, Australia. No eukaryotes were identified in any of these systematically l...
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.69.9.2500
更新日期:1972-09-01 00:00:00
abstract::Nitric oxide (NO) has been implicated as a pathogenic mediator in a variety of central nervous system (CNS) disease states, including the animal model of multiple sclerosis (MS) and experimental allergic encephalomyelitis. We have examined post-mortem brain tissues collected from patients previously diagnosed with MS,...
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.92.26.12041
更新日期:1995-12-19 00:00:00
abstract::(3)H-actinomycin D, a guanine-binding agent, labels fixed human chromosomes nonrandomly. Actinomycin D added in G2 inhibits secondary constrictions and breaks chromosomes. There is some tendency for label to be concentrated at the ends of chromosomes and near the centromere. Labeling with (3)H-thymidine in the late st...
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.65.3.585
更新日期:1970-03-01 00:00:00
abstract::Metallic nanoscale structures are capable of supporting surface plasmon polaritons (SPPs), propagating collective electron oscillations with tight spatial confinement at the metal surface. SPPs represent one of the most promising structures to beat the diffraction limit imposed by conventional dielectric optics. Ag na...
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.0902064106
更新日期:2009-12-15 00:00:00
abstract::Viral hepatitis is a disease of antiquity, but evidence for more than one etiologic agent has been recognized only since the 1940s, when two viruses (hepatitis A virus and hepatitis B virus) were thought to account for all disease. In the past 20 years, three additional hepatitis agents (hepatitis C virus, hepatitis D...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章,评审
doi:10.1073/pnas.91.7.2401
更新日期:1994-03-29 00:00:00
abstract::A deficit in early clearance of Pseudomonas aeruginosa (P. aeruginosa) is crucial in nosocomial pneumonia and in chronic lung infections. Few studies have addressed the role of Toll-like receptors (TLRs), which are early pathogen associated molecular pattern receptors, in pathogen uptake and clearance by alveolar macr...
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.1108464109
更新日期:2012-01-31 00:00:00
abstract::Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 (V(1393)I, K(1584)E) were predicted to confer susceptibility for DM2. Here, we show using patch...
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.1113811109
更新日期:2012-07-10 00:00:00
abstract::Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a disti...
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.0503218102
更新日期:2005-06-14 00:00:00
abstract::I have determined the nucleotide sequence of the ampicillin resistance gene of pBR322, an Escherichia coli plasmid that encodes a penicillin beta-lactamase. This gene codes for a protein of 286 amino acid residues. The first 23 amino acids presumably form a signal for secretion, because they do not appear in the matur...
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.75.8.3737
更新日期:1978-08-01 00:00:00
abstract::Type 2 diabetes mellitus (T2DM) is strongly associated with obesity in most, but not all, ethnic groups, suggesting important ethnic differences in disease susceptibility. Although it is clear that insulin resistance plays a major role in the pathogenesis of T2DM and that insulin resistance is strongly associated with...
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.0608537103
更新日期:2006-11-28 00:00:00
abstract::Transcriptional activation of cytochrome P450 (CYP) genes and various drug metabolizing enzymes by the prototypical inducer phenobarbital (PB) and many other drugs and chemicals is an adaptive response of the organism to exposure to xenobiotics. The response to PB is mediated by the nuclear receptor constitutive andro...
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.0610216104
更新日期:2007-01-16 00:00:00
abstract::Management of the diverse fisheries of the world has had mixed success. While managing single species in data-rich environments has been largely effective, perhaps the greatest challenge facing fishery managers is how to deal with mixed stocks of fish with a range of life histories that reside in the same location. Be...
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.1705169114
更新日期:2017-08-22 00:00:00
abstract::One of the issues currently being debated in the ongoing discussion of the pros and cons of today's globalization concerns the effects of greater world trade as well as of the changes in technology on a country's internal distribution of income, especially on skilled versus unskilled wage rates. In this article, I att...
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.1733335100
更新日期:2003-09-16 00:00:00