Self- and co-assembly of the amyloid suppressing chaperone DNAJB6b
(2026)- Abstract
- The clustering of certain proteins into oligomers and fibrils, known as amyloids, underlies the pathology of diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. These processes are counteracted by the cellular protein quality control system, which includes molecular chaperones that interact with disease-associated proteins. One such chaperone is DNAJB6b, which has gained increasing attention over the past decades due to its observed importance in maintaining low levels of harmful protein aggregates.
This thesis aims to deepen our understanding of how DNAJB6b behaves on its own in solution and how it suppresses amyloid formation. The self-assembly of DNAJB6b was investigated under varying solution... (More) - The clustering of certain proteins into oligomers and fibrils, known as amyloids, underlies the pathology of diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. These processes are counteracted by the cellular protein quality control system, which includes molecular chaperones that interact with disease-associated proteins. One such chaperone is DNAJB6b, which has gained increasing attention over the past decades due to its observed importance in maintaining low levels of harmful protein aggregates.
This thesis aims to deepen our understanding of how DNAJB6b behaves on its own in solution and how it suppresses amyloid formation. The self-assembly of DNAJB6b was investigated under varying solution conditions, revealing that the chaperone readily forms oligomers with a broad size distribution. Monomers are in equilibrium with these oligomers, and the self-assembly resembles that of micelle formation, with an observed critical micelle concentration of approximately 120 nM at room temperature, pH 8.0, and moderate ionic strength. We found that the oligomeric state is virtually inactive in amyloid suppression compared to the dissociated monomeric subunits. We then reversed the perspective and asked which aggregation states of amyloid β are targeted by DNAJB6b. DNAJB6b was found to bind amyloid oligomers with high affinity, likely retarding their conversion into mature fibrils.
Furthermore, the amyloid-suppressive mechanism of DNAJB6b was examined for the amyloid-forming region of the tau protein, which is closely linked to the development of Alzheimer’s disease. DNAJB6b exhibited remarkably high inhibition potency, producing a pronounced delay in fibril formation at molar ratios of 1:700 chaperone to tau. Finally, we show that DNAJB6b co-aggregates with tau and binds to tau fibrils, while no detectable interaction with tau monomers was observed.
Together, these insights provide a framework for understanding how DNAJB6b may act as a potent chaperone for amyloid prone proteins. By showcasing the interplay between aggregation states, dynamics, and function, these results may inspire the design of novel therapeutic strategies to counteract protein aggregation in disease. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/cbd1a2d1-3028-47f5-ae74-86ad1b130c55
- author
- Carlsson, Andreas LU
- supervisor
-
- Sara Snogerup-Linse LU
- Thom Leiding LU
- Ingemar André LU
- opponent
-
- Professor Otzen, Daniel, Aarhus University
- organization
- alternative title
- Själv- och co-aggregering av det amyloidinhiberande chaperonet DNAJB6b
- publishing date
- 2026-02-26
- type
- Thesis
- publication status
- published
- subject
- keywords
- chaperones, amyloids, protein aggregation, Alzheimer's disease, self-assembly, neurodegenerative diseases, DNAJB6b, HSP40, tau, amyloid beta, Aβ42, protein characterization
- pages
- 82 pages
- publisher
- Lund University
- defense location
- KC:A
- defense date
- 2026-03-27 09:00:00
- ISBN
- 978-91-8104-834-6
- 978-91-8104-835-3
- language
- English
- LU publication?
- yes
- id
- cbd1a2d1-3028-47f5-ae74-86ad1b130c55
- date added to LUP
- 2026-02-26 09:53:47
- date last changed
- 2026-03-04 08:28:13
@phdthesis{cbd1a2d1-3028-47f5-ae74-86ad1b130c55,
abstract = {{The clustering of certain proteins into oligomers and fibrils, known as amyloids, underlies the pathology of diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. These processes are counteracted by the cellular protein quality control system, which includes molecular chaperones that interact with disease-associated proteins. One such chaperone is DNAJB6b, which has gained increasing attention over the past decades due to its observed importance in maintaining low levels of harmful protein aggregates.<br/><br/>This thesis aims to deepen our understanding of how DNAJB6b behaves on its own in solution and how it suppresses amyloid formation. The self-assembly of DNAJB6b was investigated under varying solution conditions, revealing that the chaperone readily forms oligomers with a broad size distribution. Monomers are in equilibrium with these oligomers, and the self-assembly resembles that of micelle formation, with an observed critical micelle concentration of approximately 120 nM at room temperature, pH 8.0, and moderate ionic strength. We found that the oligomeric state is virtually inactive in amyloid suppression compared to the dissociated monomeric subunits. We then reversed the perspective and asked which aggregation states of amyloid β are targeted by DNAJB6b. DNAJB6b was found to bind amyloid oligomers with high affinity, likely retarding their conversion into mature fibrils.<br/><br/>Furthermore, the amyloid-suppressive mechanism of DNAJB6b was examined for the amyloid-forming region of the tau protein, which is closely linked to the development of Alzheimer’s disease. DNAJB6b exhibited remarkably high inhibition potency, producing a pronounced delay in fibril formation at molar ratios of 1:700 chaperone to tau. Finally, we show that DNAJB6b co-aggregates with tau and binds to tau fibrils, while no detectable interaction with tau monomers was observed.<br/><br/>Together, these insights provide a framework for understanding how DNAJB6b may act as a potent chaperone for amyloid prone proteins. By showcasing the interplay between aggregation states, dynamics, and function, these results may inspire the design of novel therapeutic strategies to counteract protein aggregation in disease.}},
author = {{Carlsson, Andreas}},
isbn = {{978-91-8104-834-6}},
keywords = {{chaperones; amyloids; protein aggregation; Alzheimer's disease; self-assembly; neurodegenerative diseases; DNAJB6b; HSP40; tau; amyloid beta; Aβ42; protein characterization}},
language = {{eng}},
month = {{02}},
publisher = {{Lund University}},
school = {{Lund University}},
title = {{Self- and co-assembly of the amyloid suppressing chaperone DNAJB6b}},
url = {{https://lup.lub.lu.se/search/files/243358427/Thesis_e-spik.pdf}},
year = {{2026}},
}