The disordered protein SERF promotes α-Synuclein aggregation through liquid-liquid phase separation.
J Biol Chem
; 300(3): 105667, 2024 Mar.
Article
in En
| MEDLINE
| ID: mdl-38272228
ABSTRACT
The aggregation of α-Synuclein (α-Syn) into amyloid fibrils is the hallmark of Parkinson's disease. Under stress or other pathological conditions, the accumulation of α-Syn oligomers is the main contributor to the cytotoxicity. A potential approach for treating Parkinson's disease involves preventing the accumulation of these α-Syn oligomers. In this study, we present a novel mechanism involving a conserved group of disorderly proteins known as small EDRK-rich factor (SERF), which promotes the aggregation of α-Syn through a cophase separation process. Using diverse methods like confocal microscopy, fluorescence recovery after photobleaching assays, solution-state NMR spectroscopy, and Western blot, we determined that the N-terminal domain of SERF1a plays a role in the interactions that occur during cophase separation. Within these droplets, α-Syn undergoes a gradual transformation from solid condensates to amyloid fibrils, while SERF1a is excluded from the condensates and dissolves into the solution. Notably, in vivo experiments show that SERF1a cophase separation with α-Syn significantly reduces the deposition of α-Syn oligomers and decreases its cellular toxicity under stress. These findings suggest that SERF1a accelerates the conversion of α-Syn from highly toxic oligomers to less toxic fibrils through cophase separation, thereby mitigating the biological damage of α-Syn aggregation.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Parkinson Disease
/
Alpha-Synuclein
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2024
Document type:
Article
Affiliation country:
China