Role of aberrant phase separation in pathological protein aggregation

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Neurodegenerative diseases involve the pathological accumulation of intrinsically disordered proteins (IDPs).
• IDPs are increasingly recognized to form dynamic, membrane-less organelles within cells via liquid-liquid phase separation (LLPS).

Purpose of the Study:

• To discuss the role of phase separation in the pathological aggregation of key neuronal proteins linked to neurodegeneration.
• To explore the transition of biomolecular condensates to pathogenic aggregates.

Main Methods:

• Literature review and synthesis of recent evidence on protein phase separation in neurodegeneration.
• Focus on neuronal proteins: tau, alpha-synuclein, fused in sarcoma (FUS), and TDP-43.

Main Results:

• IDPs and proteins with intrinsically disordered regions undergo LLPS to form biomolecular condensates.
• These condensates can mature into pathological species like amyloid fibrils, oligomers, or amorphous aggregates.
• Phase separation is a critical mechanism linking protein dysregulation to neurodegenerative pathologies.

Conclusions:

• The phase separation of neuronal proteins like tau, alpha-synuclein, FUS, and TDP-43 is central to neurodegenerative disease pathogenesis.
• Understanding LLPS and subsequent aggregation is crucial for developing therapeutic strategies against these debilitating conditions.