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Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Protein homeostasis is essential for maintaining normal cellular function. However, protein homeostasis efficiency declines with age, leading to the accumulation of aberrant protein structures associated with neurodegenerative diseases such as Parkinson's disease (PD). PD is characterized by the aggregation of alpha-synuclein (αSyn) into cytoplasmic inclusions. This process is accompanied by elevated phosphorylation at serine 129 (S129). The accumulation of αSyn into aggregates and their propagation disrupts key proteostasis pathways, including the ubiquitin–proteasome system (UPS) or autophagy, contributing to cellular dysfunction and neuronal death. This study identified the proteasome activator Blm10 and its human ortholog PA200 as modulators of αSyn degradation and toxicity. The conserved Blm10/PA200 protein plays a key role in regulating proteasome activity and assembly. The αSyn expression increases Blm10 protein stability through autophagy inhibition, in a manner dependent on αSyn phosphorylation at S129 in yeast. Overexpression of BLM10 or PA200 reduces αSyn aggregation and enhances αSyn turnover via activation of the 20S proteasome in yeast and mammalian cells. Blm10 and PA200-capped 20S proteasomes efficiently degrade both monomeric as well as oligomeric αSyn in vitro. Notably, capped proteasomes retain proteolytic activities in the presence of αSyn, indicating resistance to αSyn-induced inhibition, in contrast to 20S or 26S proteasomes. These results reveal a distinct proteasome subtype that bypasses UPS impairment and restores proteolytic capacity under proteotoxic stress. Our findings establish Blm10/PA200 as critical regulators of αSyn proteostasis and highlight its protective role in maintaining protein homeostasis and cell viability under conditions of αSyn toxicity.
Author(s): Ali TT, Zhornyak A, Merghani M, Buschenlange Z, Sakata E, Outeiro TF, Popova B, Braus GH
Publication type: Article
Publication status: Published
Journal: Aging Cell
Year: 2026
Volume: 25
Issue: 6
Print publication date: 01/06/2026
Online publication date: 28/05/2026
Acceptance date: 05/05/2026
Date deposited: 08/06/2026
ISSN (print): 1474-9718
ISSN (electronic): 1474-9726
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1111/acel.70566
DOI: 10.1111/acel.70566
Data Access Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
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