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The catalytic nature of protein aggregation

Dear, Alexander J. ; Meisl, Georg ; Michaels, Thomas C.T. ; Zimmermann, Manuela R. ; Linse, Sara LU and Knowles, Tuomas P.J. (2020) In Journal of Chemical Physics 152(4).
Abstract

The formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking. In this paper, we therefore present a universal kinetic model for biofilament formation... (More)

The formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking. In this paper, we therefore present a universal kinetic model for biofilament formation in which every fundamental process in the reaction network can be catalytic. The single closed-form expression derived is capable of describing with high accuracy a wide range of mechanisms of biofilament formation and providing the first integrated rate law of a system in which multiple reaction processes are saturated. Moreover, its unprecedented mathematical simplicity permits us to very clearly interpret the effects of increasing saturation on the overall kinetics. The effectiveness of the model is illustrated by fitting it to the data of in vitro Aβ40 aggregation. Remarkably, we find that primary nucleation becomes saturated, demonstrating that it must be heterogeneous, occurring at interfaces and not in solution.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Physics
volume
152
issue
4
article number
045101
publisher
American Institute of Physics (AIP)
external identifiers
  • pmid:32007046
  • scopus:85078856090
ISSN
0021-9606
DOI
10.1063/1.5133635
language
English
LU publication?
yes
id
977b64d4-c848-44c9-88e2-f356d16f3ee7
date added to LUP
2020-02-11 15:51:09
date last changed
2020-08-12 03:00:30
@article{977b64d4-c848-44c9-88e2-f356d16f3ee7,
  abstract     = {<p>The formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking. In this paper, we therefore present a universal kinetic model for biofilament formation in which every fundamental process in the reaction network can be catalytic. The single closed-form expression derived is capable of describing with high accuracy a wide range of mechanisms of biofilament formation and providing the first integrated rate law of a system in which multiple reaction processes are saturated. Moreover, its unprecedented mathematical simplicity permits us to very clearly interpret the effects of increasing saturation on the overall kinetics. The effectiveness of the model is illustrated by fitting it to the data of in vitro Aβ40 aggregation. Remarkably, we find that primary nucleation becomes saturated, demonstrating that it must be heterogeneous, occurring at interfaces and not in solution.</p>},
  author       = {Dear, Alexander J. and Meisl, Georg and Michaels, Thomas C.T. and Zimmermann, Manuela R. and Linse, Sara and Knowles, Tuomas P.J.},
  issn         = {0021-9606},
  language     = {eng},
  month        = {01},
  number       = {4},
  publisher    = {American Institute of Physics (AIP)},
  series       = {Journal of Chemical Physics},
  title        = {The catalytic nature of protein aggregation},
  url          = {http://dx.doi.org/10.1063/1.5133635},
  doi          = {10.1063/1.5133635},
  volume       = {152},
  year         = {2020},
}