14-3-3τ as a Modulator of Early α-Synuclein Multimerization and Amyloid Formation

Gobert Heesink, Maxime C.M. van den Oetelaar, Slav A. Semerdzhiev, Christian Ottmann, Luc Brunsveld, Christian Blum*, Mireille M.A.E. Claessens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Downloads (Pure)

Abstract

The aggregation of α-synuclein (αS) plays a key role in Parkinson’s disease (PD) etiology. While the onset of PD is age-related, the cellular quality control system appears to regulate αS aggregation throughout most human life. Intriguingly, the protein 14-3-3τ has been demonstrated to delay αS aggregation and the onset of PD in various models. However, the molecular mechanisms behind this delay remain elusive. Our study confirms the delay in αS aggregation by 14-3-3τ, unveiling a concentration-dependent relation. Utilizing microscale thermophoresis (MST) and single-molecule burst analysis, we quantified the early αS multimers and concluded that these multimers exhibit properties that classify them as nanoscale condensates that form in a cooperative process, preceding the critical nucleus for fibril formation. Significantly, the αS multimer formation mechanism changes dramatically in the presence of scaffold protein 14-3-3τ. Our data modeling suggests that 14-3-3τ modulates the multimerization process, leading to the creation of mixed multimers or co-condensates, comprising both αS and 14-3-3τ. These mixed multimers form in a noncooperative process. They are smaller, more numerous, and distinctively not on the pathway to amyloid formation. Importantly, 14-3-3τ thus acts in the very early stage of αS multimerization, ensuring that αS does not aggregate but remains soluble and functional. This offers long-sought novel entries for the pharmacological modulation of PD.

Original languageEnglish
Pages (from-to)1926-1936
Number of pages11
JournalACS chemical neuroscience
Volume15
Issue number9
Early online date18 Apr 2024
DOIs
Publication statusPublished - 1 May 2024

Keywords

  • UT-Hybrid-D
  • IDP multimerization
  • modulation of multimerization
  • protein co-condensation
  • protein-protein interactions
  • α-synuclein aggregation
  • 14-3-3 chaperone

Fingerprint

Dive into the research topics of '14-3-3τ as a Modulator of Early α-Synuclein Multimerization and Amyloid Formation'. Together they form a unique fingerprint.

Cite this