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

bioRxiv (Cold Spring Harbor Laboratory)

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 7

1. Celia Fricke

   Technical University of Denmark

   Affiliation as printed

   Technical University of Denmark;

   Technical University of Denmark

2. Antonín Kunka

   Technical University of Denmark

   Affiliation as printed

   Technical University of Denmark;

   Technical University of Denmark

3. Rasmus K. Norrild

   Technical University of Denmark

   Affiliation as printed

   Technical University of Denmark;

   Technical University of Denmark

4. Shuangyan Wang

   Technical University of Denmark

   Affiliation as printed

   Technical University of Denmark;

   Technical University of Denmark

5. Anne S. Wentink Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry, Leiden University

6. Bernd Bukau

   German Cancer Research Center · Heidelberg University · DKFZ-ZMBH Alliance

   Affiliation as printed

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

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

7. Alexander Kai Buell corresponding

   Technical University of Denmark

   Affiliation as printed

   Technical University of Denmark;

   Technical University of Denmark