Hsp10 Targets the C-Terminus of α-Synuclein to Inhibit Secondary Nucleation and Remodel Labile Fibrils
- 1The University of Arizona
Abstract
Aggregation of a-synuclein is a central pathological feature of Parkinsons disease and related synucleinopathies. The co-chaperonin Hsp10, a component of the Hsp60/Hsp10 chaperonin system, has recently been proposed to possess independent chaperone activity and has been found to co-localize with a-synuclein aggregates in diseased brains, suggesting a role in regulating a-synuclein assembly. Here, we combine solution NMR spectroscopy, cryo-electron microscopy, and kinetic analyses to define a multistage mechanism by which Hsp10 modulates a-synuclein aggregation. Hsp10 transiently interacts with monomeric a-synuclein, with residues on the inner surface and top-loop regions of Hsp10 primarily engaging the acidic C-terminal region of a-synuclein. Hsp10 exerts a concentration-dependent, biphasic effect on aggregation, accelerating fibrillization at substoichiometric concentrations while inhibiting de novo aggregation at higher concentrations through suppression of secondary nucleation. Furthermore, Hsp10 decorates fibril surfaces through interactions with the exposed a-synuclein C-terminus, thereby limiting secondary nucleation. Hsp10 also promotes the disaggregation of thermodynamically labile fibrillar fragments. Together, these findings establish a mechanistic framework for Hsp10-mediated regulation of a-synuclein assembly and expand the functional landscape of Hsp10 beyond its canonical role in mitochondrial protein folding.
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BibTeX
@misc{hegetschweiler2026hsp10,
title = {{Hsp10 Targets the C-Terminus of α-Synuclein to Inhibit Secondary Nucleation and Remodel Labile Fibrils}},
author = {M. A. Hegetschweiler and M. S. Oliyantakath Hassan and S. Call and A. T. Adegbenro and J. Villarreal},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.760823},
url = {https://www.biorxiv.org/content/10.64898/2026.10.23.760823v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Hsp10 Targets the C-Terminus of α-Synuclein to Inhibit Secondary Nucleation and Remodel Labile Fibrils
AU - M. A. Hegetschweiler
AU - M. S. Oliyantakath Hassan
AU - S. Call
AU - A. T. Adegbenro
AU - J. Villarreal
PY - 2026
DA - 2026/10/23
PB - bioRxiv
DO - 10.64898/2026.10.23.760823
UR - https://www.biorxiv.org/content/10.64898/2026.10.23.760823v1
AB - Aggregation of a-synuclein is a central pathological feature of Parkinsons disease and related synucleinopathies. The co-chaperonin Hsp10, a component of the Hsp60/Hsp10 chaperonin system, has recently been proposed to possess independent chaperone activity and has been found to co-localize with a-synuclein aggregates in diseased brains, suggesting a role in regulating a-synuclein assembly. Here, we combine solution NMR spectroscopy, cryo-electron microscopy, and kinetic analyses to define a multistage mechanism by which Hsp10 modulates a-synuclein aggregation. Hsp10 transiently interacts with monomeric a-synuclein, with residues on the inner surface and top-loop regions of Hsp10 primarily engaging the acidic C-terminal region of a-synuclein. Hsp10 exerts a concentration-dependent, biphasic effect on aggregation, accelerating fibrillization at substoichiometric concentrations while inhibiting de novo aggregation at higher concentrations through suppression of secondary nucleation. Furthermore, Hsp10 decorates fibril surfaces through interactions with the exposed a-synuclein C-terminus, thereby limiting secondary nucleation. Hsp10 also promotes the disaggregation of thermodynamically labile fibrillar fragments. Together, these findings establish a mechanistic framework for Hsp10-mediated regulation of a-synuclein assembly and expand the functional landscape of Hsp10 beyond its canonical role in mitochondrial protein folding.
ER -