Protein misfolding and amyloid nucleation through liquid-liquid phase separation

Area of Science:

• Cell Physiology
• Neurodegenerative Diseases
• Protein Biochemistry

Background:

• Liquid-liquid phase separation (LLPS) is increasingly recognized in cellular functions and disease states.
• Intrinsically disordered regions in proteins facilitate LLPS, a common feature in proteins linked to neurodegeneration.
• Aggregation-prone proteins can undergo phase separation, forming concentrated, liquid-like droplets.

Purpose of the Study:

• To elaborate on the nucleation mechanism of amyloid aggregation via LLPS.
• To explore early molecular events in aberrant protein phase separation related to neurodegeneration.
• To summarize advancements in understanding phase transitions of key neurodegenerative disease proteins.

Main Methods:

• Review of recent literature on LLPS and amyloid aggregation.
• Analysis of molecular events linking phase separation to protein misfolding and fibril formation.
• Focus on common disease-associated factors influencing aberrant protein phase transitions.

Main Results:

• High local protein concentration within LLPS droplets drives transitions to solid-like states and nucleates amyloid fibrils.
• Protein misfolding, oligomerization, and amyloid aggregation are initiated by LLPS of neurodegeneration-related proteins.
• Genetic and environmental factors promoting neurodegeneration directly influence amyloid aggregation following phase separation.

Conclusions:

• LLPS is proposed as a prominent nucleation mechanism for aberrant protein aggregation in neurodegenerative diseases.
• A generic LLPS-mediated multistep nucleation mechanism for amyloid aggregation is suggested.
• Understanding LLPS is crucial for elucidating the implications of aberrant protein aggregation in neurodegeneration.