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The Role of α-Synuclein-DNAJB6b Coaggregation in Amyloid Suppression

Pálmadóttir, Tinna LU ; Getachew, Josef LU orcid ; Thacker, Dev LU ; Wallerstein, Johan LU orcid ; Olsson, Ulf LU orcid ; Emanuelsson, Cecilia LU orcid and Linse, Sara LU (2025) In ACS Chemical Neuroscience 16(10). p.1883-1897
Abstract

Chaperones may retard the aggregation of other proteins and increase their solubility. An important goal is a thermodynamic understanding of such an action. Here, the chaperone DNAJB6b (JB6) is found to suppress amyloid formation of the protein α-synuclein (α-syn) leading to a reduced rate of fibril formation and an increase in apparent solubility of α-syn. These findings were reached at mildly acidic pH and with light seeding under conditions where the effect on secondary nucleation is visible. Cryo-transmission electron microscopy (cryo-TEM) imaging reveals that coaggregates of α-syn and JB6 are formed with significantly altered ultrastructure compared to both pure protein fibrils and pure chaperone aggregates. This is further... (More)

Chaperones may retard the aggregation of other proteins and increase their solubility. An important goal is a thermodynamic understanding of such an action. Here, the chaperone DNAJB6b (JB6) is found to suppress amyloid formation of the protein α-synuclein (α-syn) leading to a reduced rate of fibril formation and an increase in apparent solubility of α-syn. These findings were reached at mildly acidic pH and with light seeding under conditions where the effect on secondary nucleation is visible. Cryo-transmission electron microscopy (cryo-TEM) imaging reveals that coaggregates of α-syn and JB6 are formed with significantly altered ultrastructure compared to both pure protein fibrils and pure chaperone aggregates. This is further supported by the formation of ThT-negative aggregates and by the depletion of JB6 from solution in the presence of α-syn. The identification of such coaggregates provides a plausible thermodynamic explanation for an increase in α-syn solubility in the presence of JB6; the reduced chemical potential of the chaperone upon formation of coaggregates can compensate for an increased chemical potential of α-syn, and the system as a whole can lower its free energy to sustain an increased free α-syn concentration.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aggregation equilibrium, aggregation rate, chaperone action, coaggregation, self-assembly, solubility enhancement
in
ACS Chemical Neuroscience
volume
16
issue
10
pages
15 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:105004017078
  • pmid:40304428
ISSN
1948-7193
DOI
10.1021/acschemneuro.4c00883
language
English
LU publication?
yes
id
c4a070e9-8599-424e-8e27-7483f0ecd353
date added to LUP
2025-08-01 10:47:08
date last changed
2025-08-15 12:01:28
@article{c4a070e9-8599-424e-8e27-7483f0ecd353,
  abstract     = {{<p>Chaperones may retard the aggregation of other proteins and increase their solubility. An important goal is a thermodynamic understanding of such an action. Here, the chaperone DNAJB6b (JB6) is found to suppress amyloid formation of the protein α-synuclein (α-syn) leading to a reduced rate of fibril formation and an increase in apparent solubility of α-syn. These findings were reached at mildly acidic pH and with light seeding under conditions where the effect on secondary nucleation is visible. Cryo-transmission electron microscopy (cryo-TEM) imaging reveals that coaggregates of α-syn and JB6 are formed with significantly altered ultrastructure compared to both pure protein fibrils and pure chaperone aggregates. This is further supported by the formation of ThT-negative aggregates and by the depletion of JB6 from solution in the presence of α-syn. The identification of such coaggregates provides a plausible thermodynamic explanation for an increase in α-syn solubility in the presence of JB6; the reduced chemical potential of the chaperone upon formation of coaggregates can compensate for an increased chemical potential of α-syn, and the system as a whole can lower its free energy to sustain an increased free α-syn concentration.</p>}},
  author       = {{Pálmadóttir, Tinna and Getachew, Josef and Thacker, Dev and Wallerstein, Johan and Olsson, Ulf and Emanuelsson, Cecilia and Linse, Sara}},
  issn         = {{1948-7193}},
  keywords     = {{aggregation equilibrium; aggregation rate; chaperone action; coaggregation; self-assembly; solubility enhancement}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1883--1897}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Neuroscience}},
  title        = {{The Role of α-Synuclein-DNAJB6b Coaggregation in Amyloid Suppression}},
  url          = {{http://dx.doi.org/10.1021/acschemneuro.4c00883}},
  doi          = {{10.1021/acschemneuro.4c00883}},
  volume       = {{16}},
  year         = {{2025}},
}