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PreprintCited by 7Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsHeat shock proteins research

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Thermodynamic Stability Modulates Chaperone-Mediated Disaggregation of α-Synuclein Fibrils

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Fricke, Celia, Kunka, Antonin, Norrild, Rasmus K., Wang, Shuang-Yan, Dang, Thi Lieu, Wentink, Anne S., Bukau, Bernd, Buell, Alexander K.·2024·Chemical Science
DOI 10.1101/2024.12.19.629136PMC PMC12622358

Preprint — published as 10.1039/d5sc04927j

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Abstract

The aggregation of the intrinsically disordered protein alpha-synuclein into amyloid fibrils and their subsequent intracellular accumulation are characteristic features of several neurodegenerative disorders, such as Parkinson’s disease. Currently, there are no curative treatment options available. In this study, we demonstrate that the thermodynamic stability of alpha-synuclein fibrils is a crucial factor influencing the efficiency with which they are disaggregated by the human chaperone system comprising HSP70, DNAJB1, and Apg2. We quantify the increasing stability of alpha-synuclein fibrils formed under four different solution conditions over a three-month incubation period. The chaperone system effectively disaggregates three out of the four fibril types, with varying efficiencies that correlate with their thermodynamic stability. The fibrils exhibit differential sensitivities to chaperone-mediated depolymerization, suggesting that both structural features and thermodynamic stability contribute to the susceptibility of alpha-synuclein fibrils to chaperone disaggregation. Our findings thus reveal a connection between the thermodynamic stability of fibrils and their susceptibility to chaperone-mediated disaggregation.

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Metadata

Authors
Fricke, C., Kunka, A., Norrild, R. K., Wang, S.-Y., Dang, T. L., Wentink, A. S., Bukau, B., & Buell, A. K.
Affiliations
  • Technical University of Denmark (DK)
  • Heidelberg University (DE)
  • Leiden University (NL)
Corresponding author
Buell, Alexander K.
ORCID
Venue
Chemical Science
Publisher
openRxiv
Published
2024-12-21
Volume
17
Issue
1
Pages
283-298
ISSN
2041-6520 (ISSN-L)
DOI
10.1101/2024.12.19.629136
PMC
PMC12622358
OpenAlex
W4416295850
Cited by
7
References
1
Citations by year
2026: 5 · 2025: 2
FWCI
4.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Chemical Science (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by-nc)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
Funders
  • European Commission (101106115, 101088163 EMMA, ERC CoG 101088163, 101088163, ERC CoG 101088163 EMMA)
  • Deutsche Forschungsgemeinschaft (504257241)
  • Lundbeckfonden (R366-2021-169)
  • Novo Nordisk
  • Novo Nordisk Fonden (NNF21OC0065495, NNF17SA0028392)
  • H. Lundbeck A/S
  • National Institutes of Health
  • European Research Council (101088163)
  • National Institute on Aging (U24AG079685)
  • National Institute of Neurological Disorders and Stroke (R01NS119689)
  • HORIZON EUROPE Marie Sklodowska-Curie Actions (101106115)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
alpha-synuclein, fibril disaggregation, thermodynamic stability, Parkinson's disease, multiple system atrophy, protein aggregation

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