Abstract:
:The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chemical kinetics to investigate their dynamical properties. By fitting experimental data for several unrelated amyloidogenic systems to newly derived mechanistic models, we find that oligomers present with a remarkably wide range of kinetic and thermodynamic stabilities but that they possess two properties that are generic: they are overwhelmingly nonfibrillar, and they predominantly dissociate back to monomers rather than maturing into fibrillar species. These discoveries change our understanding of the relationship between amyloid oligomers and amyloid fibrils and have important implications for the nature of their cellular toxicity.
journal_name
Proc Natl Acad Sci U S Aauthors
Dear AJ,Michaels TCT,Meisl G,Klenerman D,Wu S,Perrett S,Linse S,Dobson CM,Knowles TPJdoi
10.1073/pnas.1922267117subject
Has Abstractpub_date
2020-06-02 00:00:00pages
12087-12094issue
22eissn
0027-8424issn
1091-6490pii
1922267117journal_volume
117pub_type
杂志文章abstract::The three lipin phosphatidate phosphatase (PAP) enzymes catalyze a step in glycerolipid biosynthesis, the conversion of phosphatidate to diacylglycerol. Lipin-1 is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves. Little is known about the physiological role of lipin...
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.1205221109
更新日期:2012-09-11 00:00:00
abstract::Transplanted cord blood (CB) hematopoietic stem cells (HSC) and progenitor cells (HPC) can treat malignant and nonmalignant disorders. Because long-term cryopreservation is critical for CB banking and transplantation, we assessed the efficiency of recovery of viable HSCHPC from individual CBs stored frozen for 15 yr. ...
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.0237086100
更新日期:2003-01-21 00:00:00
abstract::DNA "breathing" is a thermally driven process in which base-paired DNA sequences transiently adopt local conformations that depart from their most stable structures. Polymerases and other proteins of genome expression require access to single-stranded DNA coding templates located in the double-stranded DNA "interior,"...
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.1314862110
更新日期:2013-10-22 00:00:00
abstract::The pH gradient (delta pH) across the membrane of bovine neurohypophysial granules was estimated by using the [14C]methylamine partition technique. The granule membrane showed high permeability to sugars such as sucrose or sorbitol and to cations. Granules suspended in sucrose medium showed an acidic internal delta pH...
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.79.2.476
更新日期:1982-01-01 00:00:00
abstract::Mechanism of enzymatic conversion of a fatty acid to the corresponding alkane by the loss of the carboxyl carbon was investigated with particulate preparations from Pisum sativum. A heavy particulate preparation (sp. gr., 1.30 g/cm3) isolated by two density-gradient centrifugation steps catalyzed conversion of octadec...
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.81.21.6613
更新日期:1984-11-01 00:00:00
abstract::A paradigm of evolutionary biology is that adaptation and reproductive isolation are caused by a nearly infinite number of mutations of individually small effect. Here, we test this hypothesis by investigating the genetic basis of pollinator discrimination in two closely related species of monkeyflowers that differ in...
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.96.21.11910
更新日期:1999-10-12 00:00:00
abstract::During mammalian aging, cellular proteins become increasingly damaged: for example, by carbonylation and formation of advanced glycation end products (AGEs). The means to ensure that offspring are born without such damage are unknown. Unexpectedly, we found that undifferentiated mouse ES cells contain high levels of 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.0510944103
更新日期:2006-05-16 00:00:00
abstract::Because neurogenesis persists in the adult mammalian brain and can be regulated by physiological and pathological events, we investigated its possible involvement in the brain's response to focal cerebral ischemia. Ischemia was induced by occlusion of the middle cerebral artery in the rat for 90 min, and proliferating...
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.081011098
更新日期:2001-04-10 00:00:00
abstract::The Ah receptor (AHR) is a basic helix-loop-helix protein that mediates the effects of 2,3,7,8-tetrachloro-dibenzo-p-dioxin. In this report, we describe a rabbit reticulocyte system that allows functional expression of both the AHR and its dimeric partner, the AHR nuclear translocator protein (ARNT). By using this in ...
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.90.18.8566
更新日期:1993-09-15 00:00:00
abstract::The interaction between DNA polymerases and sliding clamp proteins confers processivity in DNA synthesis. This interaction is critical for most DNA replication machines from viruses and prokaryotes to higher eukaryotes. The clamp proteins also participate in a variety of dynamic and competing protein-protein interacti...
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.191384398
更新日期:2001-09-25 00:00:00
abstract::Previous studies have demonstrated that mutation in the forkhead domain of the forkhead box P2 (FOXP2) protein (R553H) causes speech-language disorders. To further analyze FOXP2 function in speech learning, we generated a knockin (KI) mouse for Foxp2 (R552H) [Foxp2 (R552H)-KI], corresponding to the human FOXP2 (R553H)...
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.0712298105
更新日期:2008-02-26 00:00:00
abstract::Both mammals and birds use the interaural time difference (ITD) for localization of sound in the horizontal plane. They may localize either real or phantom sound sources, when the signal consists of a narrow frequency band. This ambiguity does not occur with broadband signals. A plot of impulse rates or amplitude of 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.97.22.11787
更新日期:2000-10-24 00:00:00
abstract::Population growth rate is a fundamental ecological and evolutionary characteristic of living organisms, but individuals must balance the metabolism devoted to biosynthesis and reproduction against the maintenance of existing structure and other functionality. Here we present a mathematical model that relates metabolic...
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.1115585109
更新日期:2012-01-10 00:00:00
abstract::Escherichia coli phage N4 transcription is resistant to rifampicin, an inhibitor of the host RNA polymerase, even when the drug is added prior to infection. A rifampicin-resistant RNA polymerase has been detected in disrupted N4 virions. This enzyme shows a requirement for the four ribonucleoside 5'-triphosphates and ...
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.74.2.520
更新日期:1977-02-01 00:00:00
abstract::An excised patch of embryonic muscle membrane was used as a probe for measuring the release of acetylcholine (AcCho) from growing spinal neurons in Xenopus cell culture. The neuron was stimulated extracellularly at the soma, and the evoked AcCho release was monitored at the growth cone, along the neurite, and near the...
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.84.8.2540
更新日期:1987-04-01 00:00:00
abstract::The emergence of the nematic electronic state that breaks rotational symmetry is one of the most fascinating properties of the iron-based superconductors, and has relevance to cuprates as well. FeSe has a unique ground state in which superconductivity coexists with a nematic order without long-range magnetic ordering,...
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.1717331115
更新日期:2018-02-06 00:00:00
abstract::The understanding of mechanisms controlling zinc absorption and metabolism at the molecular level has advanced recently. Kinetics of zinc transport have been investigated for many years, but only recently have genes coding for proteins thought to be involved in the transport process been cloned. Four putative zinc tra...
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.95.9.4841
更新日期:1998-04-28 00:00:00
abstract::A key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and transcriptional coactivators. Seemingly incongruent with the tight regulation of transcription, many biochemical and biophysical studies suggest that activators u...
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.2013244117
更新日期:2020-11-03 00:00:00
abstract::For the emergence of early life, the formation of biopolymers such as RNA is essential. However, the addition of nucleotide monomers to existing oligonucleotides requires millimolar concentrations. Even in such optimistic settings, no polymerization of RNA longer than about 20 bases could be demonstrated. How then cou...
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.1303222110
更新日期:2013-05-14 00:00:00
abstract::Gaseous HCl generated from a variety of sources is ubiquitous in both outdoor and indoor air. Oxides of nitrogen (NO(y)) are also globally distributed, because NO formed in combustion processes is oxidized to NO(2), HNO(3), N(2)O(5) and a variety of other nitrogen oxides during transport. Deposition of HCl and NO(y) o...
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.0904195106
更新日期:2009-08-18 00:00:00
abstract::A distinct phosphodiesterasic activity (EC 3.1.4) was found in both mono- and dicotyledonous plants that catalyzes the hydrolytic breakdown of ADPglucose (ADPG) to produce equimolar amounts of glucose-1-phosphate and AMP. The enzyme responsible for this activity, referred to as ADPG pyrophosphatase (AGPPase), was puri...
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.120168097
更新日期:2000-07-18 00:00:00
abstract::Helminthosporoside is a host-specific toxin produced by Helminthosporium sacchari, both in culture and in infected sugarcane tissue. The susceptibility of any given clone of sugarcane to disease is invariably associated with the presence of a toxin-binding protein. This report presents evidence for the presence of the...
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.71.4.1413
更新日期:1974-04-01 00:00:00
abstract::Downstream placement of a strong transcriptional termination signal has made possible the cloning of bacteriophage T5 promoters known to exhibit high signal strength. The cloning system constructed contains two easily assayable indicator functions whose expression is controlled by the integration of promoters and term...
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.78.8.4936
更新日期:1981-08-01 00:00:00
abstract::To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, 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.1404386111
更新日期:2014-10-28 00:00:00
abstract::Loquacious-PD (Loqs-PD) is required for biogenesis of many endogenous siRNAs in Drosophila In vitro, Loqs-PD enhances the rate of dsRNA cleavage by Dicer-2 and also enables processing of substrates normally refractory to cleavage. Using purified components, and Loqs-PD truncations, we provide a mechanistic basis for 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.1707063114
更新日期:2017-09-19 00:00:00
abstract::Advanced personalized medical diagnostics depend on the availability of high-quality biological samples. These are typically biofluids, such as blood, saliva, or urine; and their collection and storage is critical to obtain reliable results. Without proper temperature regulation, protein biomarkers in particular can d...
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.1602493113
更新日期:2016-05-24 00:00:00
abstract::The yeast SIN1 protein is a nuclear protein that together with other proteins behaves as a transcriptional repressor of a family of genes. In addition, sin1 mutants are defective in proper mitotic chromosome segregation. In an effort to understand the basis for these phenotypes, we employed the yeast two-hybrid system...
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.93.16.8274
更新日期:1996-08-06 00:00:00
abstract::Suppressor T cells have been shown to be much more radiosensitive than other lymphoïd cells, and we have tried to reduce tumor growth by low-dose irradiation. Syngeneic DBA/2 mice received whole-body irradiation (150 rads; 1 rad = 0.01 J/kg) 6 days after P815 tumor inoculation. Tumor growth is significantly reduced in...
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.78.3.1809
更新日期:1981-03-01 00:00:00
abstract::Although it has long been recognized that the enteric community of bacteria that inhabit the human distal intestinal track broadly impacts human health, the biochemical details that underlie these effects remain largely undefined. Here, we report a broad MS-based metabolomics study that demonstrates a surprisingly lar...
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.0812874106
更新日期:2009-03-10 00:00:00
abstract::Guanylin and uroguanylin are intestinal peptides that stimulate chloride secretion by activating a common set of receptor-guanylate cyclase signaling molecules located on the mucosal surface of enterocytes. High mucosal acidity, similar to the pH occurring within the fluid microclimate domain at the mucosal surface of...
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.94.6.2705
更新日期:1997-03-18 00:00:00