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Kinetic models reveal the interplay of protein production and aggregation

Wei, Jiapeng ; Meisl, Georg ; Dear, Alexander LU ; Oosterhuis, Matthijs ; Melki, Ronald ; Emanuelsson, Cecilia LU orcid ; Linse, Sara LU and Knowles, Tuomas P.J. (2024) In Chemical Science
Abstract

Protein aggregation is a key process in the development of many neurodegenerative disorders, including dementias such as Alzheimer's disease. Significant progress has been made in understanding the molecular mechanisms of aggregate formation in pure buffer systems, much of which was enabled by the development of integrated rate laws that allowed for mechanistic analysis of aggregation kinetics. However, in order to translate these findings into disease-relevant conclusions and to make predictions about the effect of potential alterations to the aggregation reactions by the addition of putative inhibitors, the current models need to be extended to account for the altered situation encountered in living systems. In particular, in vivo,... (More)

Protein aggregation is a key process in the development of many neurodegenerative disorders, including dementias such as Alzheimer's disease. Significant progress has been made in understanding the molecular mechanisms of aggregate formation in pure buffer systems, much of which was enabled by the development of integrated rate laws that allowed for mechanistic analysis of aggregation kinetics. However, in order to translate these findings into disease-relevant conclusions and to make predictions about the effect of potential alterations to the aggregation reactions by the addition of putative inhibitors, the current models need to be extended to account for the altered situation encountered in living systems. In particular, in vivo, the total protein concentrations typically do not remain constant and aggregation-prone monomers are constantly being produced but also degraded by cells. Here, we build a theoretical model that explicitly takes into account monomer production, derive integrated rate laws and discuss the resulting scaling laws and limiting behaviours. We demonstrate that our models are suited for the aggregation-prone Huntington's disease-associated peptide HttQ45 utilizing a system for continuous in situ monomer production and the aggregation of the tumour suppressor protein P53. The aggregation-prone HttQ45 monomer was produced through enzymatic cleavage of a larger construct in which a fused protein domain served as an internal inhibitor. For P53, only the unfolded monomers form aggregates, making the unfolding a rate-limiting step which constitutes a source of aggregation-prone monomers. The new model opens up possibilities for a quantitative description of aggregation in living systems, allowing for example the modelling of inhibitors of aggregation in a dynamic environment of continuous protein synthesis.

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organization
publishing date
type
Contribution to journal
publication status
in press
subject
in
Chemical Science
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85192991316
ISSN
2041-6520
DOI
10.1039/d4sc00088a
language
English
LU publication?
yes
id
447c9685-0934-48ba-9a6f-f69acb789a00
date added to LUP
2024-05-29 15:39:29
date last changed
2024-05-30 12:54:05
@article{447c9685-0934-48ba-9a6f-f69acb789a00,
  abstract     = {{<p>Protein aggregation is a key process in the development of many neurodegenerative disorders, including dementias such as Alzheimer's disease. Significant progress has been made in understanding the molecular mechanisms of aggregate formation in pure buffer systems, much of which was enabled by the development of integrated rate laws that allowed for mechanistic analysis of aggregation kinetics. However, in order to translate these findings into disease-relevant conclusions and to make predictions about the effect of potential alterations to the aggregation reactions by the addition of putative inhibitors, the current models need to be extended to account for the altered situation encountered in living systems. In particular, in vivo, the total protein concentrations typically do not remain constant and aggregation-prone monomers are constantly being produced but also degraded by cells. Here, we build a theoretical model that explicitly takes into account monomer production, derive integrated rate laws and discuss the resulting scaling laws and limiting behaviours. We demonstrate that our models are suited for the aggregation-prone Huntington's disease-associated peptide HttQ45 utilizing a system for continuous in situ monomer production and the aggregation of the tumour suppressor protein P53. The aggregation-prone HttQ45 monomer was produced through enzymatic cleavage of a larger construct in which a fused protein domain served as an internal inhibitor. For P53, only the unfolded monomers form aggregates, making the unfolding a rate-limiting step which constitutes a source of aggregation-prone monomers. The new model opens up possibilities for a quantitative description of aggregation in living systems, allowing for example the modelling of inhibitors of aggregation in a dynamic environment of continuous protein synthesis.</p>}},
  author       = {{Wei, Jiapeng and Meisl, Georg and Dear, Alexander and Oosterhuis, Matthijs and Melki, Ronald and Emanuelsson, Cecilia and Linse, Sara and Knowles, Tuomas P.J.}},
  issn         = {{2041-6520}},
  language     = {{eng}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{Chemical Science}},
  title        = {{Kinetic models reveal the interplay of protein production and aggregation}},
  url          = {{http://dx.doi.org/10.1039/d4sc00088a}},
  doi          = {{10.1039/d4sc00088a}},
  year         = {{2024}},
}