α-Synuclein liquid condensates fuel fibrillar α-synuclein growth

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Alpha-synuclein (α-Syn) aggregation is linked to Lewy pathology and synucleinopathies.
• Emerging evidence suggests α-Syn forms liquid condensates via phase separation, but their role in aggregation and disease is unclear.
• The interaction between α-Syn fibrils and condensates is largely unexplored due to challenges in forming and studying condensates in cells.

Purpose of the Study:

• To develop a method for controlled assembly and disassembly of α-Syn condensates in cells.
• To investigate the impact of preformed α-Syn fibrillar polymorphs on these cellular condensates.
• To elucidate the interplay between α-Syn fibrils and α-Syn condensates in the context of aggregation and disease.

Main Methods:

• Developed a novel assay for inducible and reversible formation of α-Syn condensates within cells.
• Exposed cells containing α-Syn condensates to preformed α-Syn fibrillar seeds.
• Utilized microscopy and biochemical assays to analyze structural changes and aggregation dynamics.

Main Results:

• Preformed α-Syn fibrils induced liquid α-Syn condensates to transition into solid-like structures.
• These transformed structures exhibited progressive growth with needle-like extensions.
• Pathological amyloid hallmarks were observed in the fibril-induced structures, while α-Syn not undergoing phase separation remained unaffected.

Conclusions:

• Alpha-synuclein condensates can be triggered by exogenous fibrils to form pathological amyloid structures.
• α-Syn within condensates may serve as a substrate that fuels the growth of fibrillar seeds.
• This process could accelerate the prion-like propagation of pathogenic α-Syn aggregates in synucleinopathies.