# Heat shock protein 10 as a chaperone modulating α‐synuclein amyloid fibril formation

## TL;DR

This study shows that HSP10 can both prevent and promote the formation of α-synuclein fibrils, which are linked to Parkinson's disease, depending on the conditions.

## Contribution

The study reveals a dual role of HSP10 in modulating α-synuclein fibril formation under different concentration conditions.

## Key findings

- HSP10 inhibits fibril formation of α-synuclein at sufficient concentrations by binding to monomers and blocking secondary nucleation.
- Under sub-stoichiometric conditions, HSP10 promotes fibril formation of A30P α-synuclein by sequestering monomers.
- The fibril acceleration effect is specific to A30P α-synuclein and not observed with wild-type α-synuclein.

## Abstract

HSP10 is a well‐known human co‐chaperone that interacts with HSP60 to comprise the HSP60/10 chaperonin complex which upholds mitochondrial proteostasis. HSP10 also demonstrates independent roles in binding to misfolded proteins and interacts with several amyloidogenic client proteins. Using a variety of biophysical and biochemical methods, we studied the interactions of HSP10 with the amyloidogenic protein α‐synuclein (α‐syn) associated with Parkinson's disease. HSP10 efficiently inhibited fibril formation of wild type (WT) and disease‐mutant A30P α‐syn at sufficient concentrations of chaperone by both binding to α‐syn monomers and by blocking secondary nucleation on fibril surfaces. However, under sub‐stoichiometric conditions, below 1:5 (HSP10:α‐syn), the chaperone sequestered multiple A30P α‐syn monomers and thereby promoted nucleation of fibril formation with a magnitude comparable to the efficacy of seeding with preformed fibrils. The fibril formation acceleration effect of the HSP10 chaperone was client‐specific as it was observed for A30P but not WT α‐syn. Our results broaden the scope of HSP10 chaperone activity and can have implications for disease onset in synucleinopathies.