Amyloid-β modulates the phase separation and aggregation of α- synuclein

• 成果类型: Article
• 署名作者: Rontgen, Alexander; Toprakcioglu, Zenon; Morris, Owen M.; Vendruscolo, Michele
• 署名单位: University of Cambridge
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13549
• DOI: 10.1073/pnas.2501987122
• 发表日期: 2025-07-22
• 关键词: alzheimers-disease; accumulation; deposition; peptide; degradation; propagation; resistance; dementia; proteins; kinetics

摘要

The aggregation of amyloid-beta (A beta) and alpha- synuclein (alpha Syn) into insoluble proteinaceous deposits is a hallmark of Alzheimer's and Parkinson's diseases. Recent evidence suggests that these amyloidogenic proteins act in synergy, with their coaggregation frequently observed in these disorders. In this study, we investigate the interaction of A beta and alpha Syn using various biophysical tools. In particular, we explore the cocondensation of A beta with alpha Syn, elucidating the pathways through which A beta modulates alpha Syn phase separation. We studied different variants of A beta, focusing on the most prominent species, namely A beta 42 and A beta 40. We found that A beta 42 and A beta 40 have fundamentally different mechanistic effects on the kinetics of alpha Syn condensation. A beta 42 initially forms large aggregates that act as heterogeneous nucleation sites which initiate the phase separation of alpha Syn. In contrast, A beta 40 is sequestered into alpha Syn condensates where it accelerates the liquid- to- solid transition of alpha Syn into amyloid aggregates. All other A beta variants we probed fell into one of these two mechanistic pathways, with A beta 37, A beta 39, and A beta 35- 25 exhibiting similar behavior to A beta 40, whereas A beta 43 triggered nucleation processes similar to A beta 42. Given the complexity behind amyloid formation, it is key to understand how molecular partners can interact with one another. Our results thus illustrate the extreme sensitivity of protein mixtures and shed light on some of the mechanisms involved in the cocondensation and aggregation of A beta with alpha Syn.