The disordered protein SERF promotes α-Synuclein aggregation through liquid-liquid phase separation.

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Alpha-Synuclein (α-Syn) aggregation into amyloid fibrils characterizes Parkinson's disease.
• Cytotoxicity in Parkinson's disease is primarily linked to the accumulation of α-Syn oligomers under pathological conditions.

Purpose of the Study:

• To investigate the role of small EDRK-rich factor (SERF) proteins in α-Syn aggregation.
• To elucidate the mechanism by which SERF proteins influence α-Syn oligomer formation and cytotoxicity.

Main Methods:

• Confocal microscopy
• Fluorescence recovery after photobleaching (FRAP) assays
• Solution-state Nuclear Magnetic Resonance (NMR) spectroscopy
• Western blot
• In vivo experiments

Main Results:

• SERF proteins, specifically SERF1a, promote α-Syn aggregation through a cophase separation process.
• The N-terminal domain of SERF1a is crucial for interactions during cophase separation.
• SERF1a facilitates the transformation of α-Syn from toxic oligomers to less toxic fibrils.
• In vivo, SERF1a significantly reduces α-Syn oligomer deposition and cellular toxicity under stress.

Conclusions:

• SERF1a-mediated cophase separation accelerates the conversion of toxic α-Syn oligomers to less toxic fibrils.
• This mechanism mitigates the biological damage caused by α-Syn aggregation, presenting a potential therapeutic avenue for Parkinson's disease.