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

Chemical Science, vol. 17, pp. 283–298

Abstract

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.

Authors 11

1. Celia Fricke

   Technical University of Denmark

   Affiliation as printed

   Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 227, 2800 Kgs. Lyngby, Denmark

2. Antonín Kunka

   Technical University of Denmark

   Affiliation as printed

   Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 227, 2800 Kgs. Lyngby, Denmark

3. Rasmus K. Norrild

   Technical University of Denmark

   Affiliation as printed

   Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 227, 2800 Kgs. Lyngby, Denmark

4. Shuangyan Wang

   Technical University of Denmark

   Affiliation as printed

   Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 227, 2800 Kgs. Lyngby, Denmark

5. Thi Lieu Dang

   Heidelberg University · DKFZ-ZMBH Alliance

   Affiliation as printed

   Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany

6. Jonas Folke

   Frederiksberg Hospital · Bispebjerg Hospital · Copenhagen University Hospital

   Affiliation as printed

   Centre for Neuroscience and Stereology, Department of Neurology, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Nielsine Nielsens Vej 6B, Entrance 11B, Copenhagen, DK-2400, Denmark

7. Claudio A. Soto
   Affiliation as printed

   Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA

8. Susana Aznar

   Frederiksberg Hospital · Bispebjerg Hospital · Copenhagen University Hospital

   Affiliation as printed

   Centre for Neuroscience and Stereology, Department of Neurology, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Nielsine Nielsens Vej 6B, Entrance 11B, Copenhagen, DK-2400, Denmark

9. Anne S. Wentink Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, Netherlands

10. Bernd Bukau

    Heidelberg University · DKFZ-ZMBH Alliance

    Affiliation as printed

    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany

11. Alexander Kai Buell

    Technical University of Denmark

    Affiliation as printed

    Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 227, 2800 Kgs. Lyngby, Denmark