Aggregation of α-synuclein splice isoforms through a phase separation pathway.

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Alpha-synuclein (αSyn) aggregation is linked to Parkinson's disease and synucleinopathies.
• Condensation pathways involving phase-separated liquid intermediates add complexity to αSyn aggregation.
• Alternative splicing of αSyn may influence aggregate formation in disease.

Purpose of the Study:

• To compare the phase behavior of four distinct αSyn isoforms: αSyn-140, αSyn-126, αSyn-112, and αSyn-98.
• To investigate the impact of αSyn isoforms on phase separation and aggregation propensity.
• To determine if αSyn-112 affects the phase separation of αSyn-140.

Main Methods:

• Utilized confocal microscopy to visualize phase separation and aggregation.
• Employed kinetic assays to quantify aggregation rates.
• Applied microfluidic-based approaches for precise control and analysis of phase behavior.

Main Results:

• Observed significant differences in the phase separation and aggregation propensities among the four αSyn isoforms.
• Demonstrated that αSyn-112, even in small quantities, alters the phase separation of αSyn-140.
• Highlighted isoform-specific variations in the biophysical properties of αSyn.

Conclusions:

• Alternative splicing of αSyn leads to isoforms with distinct phase behaviors.
• The interplay between αSyn isoforms is crucial for understanding aggregation pathways.
• Further research is warranted to elucidate the specific roles of alternative splicing in synucleinopathies.