alpha-Synuclein fission yeast model: concentration-dependent aggregation without plasma membrane localization or...

Area of Science:

• Cell Biology
• Neuroscience
• Biochemistry

Background:

• Alpha-synuclein misfolding and aggregation are central to Parkinson's disease pathogenesis.
• Fission yeast (Schizosaccharomyces pombe) has been underutilized for modeling protein misfolding diseases.
• Budding yeast (Saccharomyces cerevisiae) offers a model for alpha-synuclein aggregation, but differences exist.

Purpose of the Study:

• To establish and characterize a fission yeast model for alpha-synuclein misfolding, aggregation, and toxicity.
• To compare alpha-synuclein behavior in fission yeast versus budding yeast.
• To investigate the nucleation-polymerization hypothesis for alpha-synuclein aggregation.

Main Methods:

• Expression of wild-type and mutant alpha-synuclein (A30P, A53T, A30P/A53T) in fission yeast using inducible promoters.
• Quantitative assessment of alpha-synuclein aggregation and localization within fission yeast cells.
• Comparison of aggregation kinetics, localization, and toxicity with existing budding yeast models.

Main Results:

• Wild-type and A53T alpha-synuclein formed intracellular cytoplasmic inclusions in fission yeast in a dose- and time-dependent manner.
• A30P and A30P/A53T mutants remained diffuse, supporting the nucleation-polymerization hypothesis.
• Unlike in budding yeast, alpha-synuclein did not localize to the plasma membrane in fission yeast, and aggregation was non-toxic.

Conclusions:

• Fission yeast provides a valuable model for studying alpha-synuclein aggregation, revealing distinct behaviors compared to budding yeast.
• The lack of plasma membrane targeting and toxicity in fission yeast offers new avenues for understanding Parkinson's disease mechanisms.
• Both fission and budding yeast models contribute complementary insights into alpha-synuclein's role in Parkinson's disease.