Phase separation and other forms of α-Synuclein self-assemblies

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Alpha-synuclein (α-Syn) aggregation into amyloid fibrils is central to Parkinson's disease (PD) and other synucleinopathies.
• The self-assembly process involves soluble monomers converting to toxic oligomers and insoluble fibrils, forming intraneuronal inclusions characteristic of PD.
• Understanding the early aggregation stages and the role of transient, neurotoxic oligomers is crucial but challenging due to their heterogeneous nature.

Approach:

• This review explores diverse α-Syn self-assembly mechanisms, focusing on recent advancements in understanding liquid-liquid phase separation (LLPS).
• LLPS is presented as an alternative nucleation pathway in the aggregation lag phase, forming dynamic supramolecular assemblies.
• The transition of these assemblies into amyloid-like hydrogels, potentially sequestering toxic species, is discussed.

Key Points:

• Soluble α-Syn oligomers are increasingly recognized as the primary neurotoxic species driving cell death in PD.
• The complex, multi-state nature of α-Syn aggregation, including metastable intermediates, complicates structure-toxicity relationship studies.
• Liquid-liquid phase separation (LLPS) provides a novel framework for understanding the initial steps of α-Syn aggregation and hydrogel formation.

Conclusions:

• Recent insights highlight LLPS as a significant mechanism in early α-Syn self-assembly, preceding fibril formation.
• Amyloid-like hydrogels formed via LLPS may act as reservoirs for toxic α-Syn oligomers and fibrils.
• Further research into LLPS-mediated α-Syn assembly is essential for elucidating PD pathogenesis and developing therapeutic strategies.