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Thermodynamic stability modulates chaperone-mediated disaggregation of α-synuclein fibrils

Aggregation of the intrinsically disordered protein alpha-synuclein into amyloid fibrils and their subsequent intracellular accumulation are hallmark features of several neurodegenerative disorders, including Parkinson's disease, for which no curative treatments currently exist. In this study,...

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Main Authors: Fricke, Celia (Author) , Kunka, Antonin (Author) , Norrild, Rasmus K. (Author) , Wang, Shuangyan (Author) , Dang, Thi-Lieu (Author) , Folke, Jonas (Author) , Shahnawaz, Mohammad (Author) , Soto, Claudio (Author) , Aznar, Susana (Author) , Wentink, Anne S. (Author) , Bukau, Bernd (Author) , Buell, Alexander K. (Author)
Format: Article (Journal)
Language:English
Published: 2026
In: Chemical science
Year: 2026, Volume: 17, Issue: 1, Pages: 283-298
ISSN:2041-6539
DOI:10.1039/D5SC04927J
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1039/D5SC04927J
Verlag, kostenfrei, Volltext: https://pubs.rsc.org/en/content/articlelanding/2026/sc/d5sc04927j
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Author Notes:Celia Fricke, Antonin Kunka, Rasmus K. Norrild, Shuangyan Wang, Thi Lieu Dang, Jonas Folke, Mohammad Shahnawaz, Claudio Soto, Susana Aznar, Anne S. Wentink, Bernd Bukau and Alexander K. Buell
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Summary:Aggregation of the intrinsically disordered protein alpha-synuclein into amyloid fibrils and their subsequent intracellular accumulation are hallmark features of several neurodegenerative disorders, including Parkinson's disease, for which no curative treatments currently exist. In this study, we investigate the relationship between fibril morphology, thermodynamic stability, and susceptibility to disaggregation by the human chaperone system comprising HSP70, DNAJB1, and Apg2. By varying assembly conditions and incubation times, we generated alpha-synuclein fibrils with diverse morphological and biochemical properties, including a broad range of thermodynamic stabilities, which we quantified using a chemical depolymerization assay. The chaperone system effectively disaggregated three of the four fibril types, with efficiencies that correlated with their thermodynamic stabilities. One fibril type resisted disaggregation despite exhibiting a comparable stability to those that were disaggregated, suggesting that additional structural features influence chaperone susceptibility. Our findings establish a quantitative link between fibril stability and chaperone-mediated disaggregation for three in vitro αSyn fibril types as well as fibrils amplified from brain extracts of PD but not MSA patients, highlighting the importance of fibril thermodynamics in biologically relevant disaggregation processes and disease pathology.
Item Description:Veröffentlicht: 11 Nov 2025
Gesehen am 04.03.2026
Physical Description:Online Resource
ISSN:2041-6539
DOI:10.1039/D5SC04927J

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