α-Synuclein aggregation, seeding and inhibition by scyllo-inositol
Tarek Ibrahim1, JoAnne McLaurin1
1Biological Sciences, Sunnybrook Research Institute, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M4N 3M5, ON, Canada.
Biochemical and Biophysical Research Communications
|December 25, 2015
Summary
Parkinson's disease (PD) protein, alpha-synuclein, aggregates faster with species-specific seeds. An inhibitor, scyllo-inositol, shows potential for slowing alpha-synuclein aggregation in PD research.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Alpha-synuclein aggregation is central to Parkinson's disease (PD) pathogenesis.
- Preformed alpha-synuclein fibrils (seeds) accelerate aggregation in vitro and in vivo.
- Conformational variants of alpha-synuclein may explain variability in experimental results.
Purpose of the Study:
- To investigate how amino acid sequence differences affect alpha-synuclein seeding efficiency.
- To compare cross-seeding kinetics between human and mouse alpha-synuclein.
- To evaluate the inhibitory potential of scyllo-inositol on alpha-synuclein aggregation.
Main Methods:
- Generation of human and mouse alpha-synuclein seeds differing by 7 amino acid residues.
- Cross-seeding kinetic studies using alpha-synuclein seeds.
- Transmission electron microscopy (TEM) to analyze aggregation and inhibition.
- In vitro assays to assess the effect of scyllo-inositol on alpha-synuclein aggregation.
Main Results:
- Mouse alpha-synuclein exhibited more rapid aggregation compared to human alpha-synuclein.
- Seeding efficiency was higher when using seeds from the same species (human or mouse).
- Scyllo-inositol demonstrated inhibitory effects on alpha-synuclein aggregation in TEM analysis.
Conclusions:
- Species-specific amino acid sequences influence alpha-synuclein seeding efficiency.
- Homologous seeding (same species) is more potent than heterologous seeding.
- Scyllo-inositol holds therapeutic promise for inhibiting alpha-synuclein aggregation in Parkinson's disease.
