Tyr39 Phosphorylation of α-Synuclein Accelerates Heterotypic Aggregation and Drives Toxic Amplification

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Parkinson's disease (PD) is linked to alpha-synuclein aggregation.
• Tyr39 phosphorylation of alpha-synuclein (pY39-α-syn) correlates with PD progression.
• The role of pY39-α-syn in synucleinopathies is not fully understood.

Purpose of the Study:

• To elucidate the mechanistic role of pY39-α-syn in alpha-synuclein aggregation and toxicity.
• To investigate how pY39-α-syn influences the aggregation pathway of wild-type alpha-synuclein (WT-α-syn).

Main Methods:

• Kinetics studies
• Continuous-wave electron paramagnetic resonance (EPR)
• Cryo-transmission electron microscopy (cryo-TEM)
• [15N,1H]-NMR spectral analyses

Main Results:

• pY39-α-syn accelerates WT-α-syn aggregation, overriding Hsc70 inhibition.
• pY39-α-syn participates in primary nucleation, forming heterotypic nuclei that drive secondary nucleation via fragmentation.
• Structurally unstable heterotypic aggregates promote toxic amplification and the formation of toxic type-B oligomers.
• Heterotypic aggregates exhibit Fenton-like activity, stabilizing Fe2+ and contributing to oxidative toxicity.

Conclusions:

• Tyr39 phosphorylation reprograms alpha-synuclein aggregation toward toxic amplification.
• pY39-α-syn plays a critical role in PD pathogenesis by promoting aggregation and oxidative stress.
• This study provides novel mechanistic insights into PD-related synucleinopathies.