SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "WFRF:(Hellstrand M) ;pers:(Knowles Tuomas P.J.)"

Sökning: WFRF:(Hellstrand M) > Knowles Tuomas P.J.

  • Resultat 1-3 av 3
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  • Cohen, Samuel I. A., et al. (författare)
  • Proliferation of amyloid-beta 42 aggregates occurs through a secondary nucleation mechanism
  • 2013
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:24, s. 9758-9763
  • Tidskriftsartikel (refereegranskat)abstract
    • The generation of toxic oligomers during the aggregation of the amyloid-beta (A beta) peptide A beta 42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer's disease, but the molecular pathways that control pathological aggregation have proved challenging to identify. Here, we use a combination of kinetic studies, selective radiolabeling experiments, and cell viability assays to detect directly the rates of formation of both fibrils and oligomers and the resulting cytotoxic effects. Our results show that once a small but critical concentration of amyloid fibrils has accumulated, the toxic oligomeric species are predominantly formed from monomeric peptide molecules through a fibril-catalyzed secondary nucleation reaction, rather than through a classical mechanism of homogeneous primary nucleation. This catalytic mechanism couples together the growth of insoluble amyloid fibrils and the generation of diffusible oligomeric aggregates that are implicated as neurotoxic agents in Alzheimer's disease. These results reveal that the aggregation of A beta 42 is promoted by a positive feedback loop that originates from the interactions between the monomeric and fibrillar forms of this peptide. Our findings bring together the main molecular species implicated in the A beta aggregation cascade and suggest that perturbation of the secondary nucleation pathway identified in this study could be an effective strategy to control the proliferation of neurotoxic A beta 42 oligomers.
  •  
2.
  • Meisl, Georg, et al. (författare)
  • Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides.
  • 2014
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:26, s. 9384-9389
  • Tidskriftsartikel (refereegranskat)abstract
    • The two major forms of the amyloid-beta (Aβ) peptide found in plaques in patients suffering from Alzheimer's disease, Aβ40 and Aβ42, only differ by two amino acids in the C-terminal region, yet they display markedly different aggregation behavior. The origins of these differences have remained challenging to connect to specific molecular-level processes underlying the aggregation reaction. In this paper we use a general strategy to apply the conventional workflow of chemical kinetics to the aggregation of the Aβ40 peptide to identify the differences between Aβ40 and Aβ42 in terms of the microscopic determinants of the aggregation reaction. Our results reveal that the major source of aggregates in the case of Aβ40 is a fibril-catalyzed nucleation process, the multistep nature of which is evident through its saturation behavior. Moreover, our results show that the significant differences in the observed behavior of the two proteins originate not simply from a uniform increase in all microscopic rates for Aβ42 compared with Aβ40, but rather are due to a shift of more than one order of magnitude in the relative importance of primary nucleation versus fibril-catalyzed secondary nucleation processes. This analysis sheds light on the microscopic determinants of the aggregation behavior of the principal forms of Aβ and outlines a general approach toward achieving an understanding at the molecular level of the aberrant deposition of insoluble peptides in neurodegenerative disorders.
  •  
3.
  • Meisl, Georg, et al. (författare)
  • Scaling behaviour and rate-determining steps in filamentous self-assembly
  • 2017
  • Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6520 .- 2041-6539. ; 8:10, s. 7087-7097
  • Tidskriftsartikel (refereegranskat)abstract
    • The formation of filaments from naturally occurring protein molecules is a process at the core of a range of functional and aberrant biological phenomena, such as the assembly of the cytoskeleton or the appearance of aggregates in Alzheimer's disease. The macroscopic behaviour associated with such processes is remarkably diverse, ranging from simple nucleated growth to highly cooperative processes with a well-defined lagtime. Thus, conventionally, different molecular mechanisms have been used to explain the self-assembly of different proteins. Here we show that this range of behaviour can be quantitatively captured by a single unifying Petri net that describes filamentous growth in terms of aggregate number and aggregate mass concentrations. By considering general features associated with a particular network connectivity, we are able to establish directly the rate-determining steps of the overall aggregation reaction from the system's scaling behaviour. We illustrate the power of this framework on a range of different experimental and simulated aggregating systems. The approach is general and will be applicable to any future extensions of the reaction network of filamentous self-assembly.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-3 av 3

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy