Modulation of α-synuclein in vitro aggregation kinetics by its alternative splice isoforms
Alexander Röntgen1, Zenon Toprakcioglu1, James E Tomkins1,2
1Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Summary
Alternative splicing of alpha-synuclein (αSyn) generates isoforms that aggregate faster than the standard form. This accelerated aggregation of αSyn-112 and αSyn-98 may contribute to Parkinson's disease pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alpha-synuclein (αSyn) misfolding and aggregation are central to synucleinopathies, including Parkinson's disease (PD).
- The SNCA gene encodes αSyn, with alternative splicing producing multiple isoforms (αSyn-140, αSyn-126, αSyn-112, αSyn-98).
Purpose of the Study:
- To investigate the biophysical characteristics of αSyn isoform aggregation.
- To elucidate the role of alternative splicing in αSyn aggregation and its potential link to synucleinopathies.
Main Methods:
- Detailed biophysical characterization of the aggregation kinetics of four αSyn isoforms.
- Transmission electron microscopy (TEM) to analyze aggregate morphology.
- Assessment of the impact of αSyn-112 on the aggregation of αSyn-140.
Main Results:
- αSyn-112 and αSyn-98 isoforms exhibit significantly accelerated aggregation kinetics compared to αSyn-140.
- Distinct aggregate morphologies were observed for the different αSyn isoforms via TEM.
- Low concentrations of αSyn-112 markedly accelerated the aggregation of αSyn-140, reducing its half-time.
Conclusions:
- Alternative splicing of αSyn plays a crucial role in modulating its aggregation process.
- The accelerated aggregation of specific αSyn isoforms suggests a novel mechanism contributing to synucleinopathy development.
- Findings provide insights into the pathological aggregation of α-synuclein and its association with Parkinson's disease.
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