Conformational distortion in a fibril-forming oligomer arrests alpha-Synuclein fibrillation and minimizes its toxic...

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alpha-Synuclein (α-Syn) aggregation into fibrils is central to Parkinson's disease pathogenesis.
• The transient, heterogeneous oligomeric forms of α-Syn are poorly understood but implicated in toxicity.
• Targeting α-Syn oligomers offers a potential therapeutic strategy for Parkinson's disease.

Purpose of the Study:

• To investigate the structural basis of α-Syn oligomer toxicity.
• To explore the potential of small molecules to modulate α-Syn aggregation and toxicity.
• To elucidate the mechanism by which heme affects α-Syn structure and function.

Main Methods:

• Utilized cryo-electron microscopy (Cryo-EM) for 3D structural reconstruction.
• Employed solid-state nuclear magnetic resonance (ssNMR) for structural motif analysis.
• Investigated the interaction of alpha-Synuclein (α-Syn) with the small molecule heme.

Main Results:

• Heme binding to α-Syn targets His50, stabilizing oligomers into a 'mace'-shaped structure.
• This heme-bound oligomer exhibits minimal toxicity compared to native aggregates.
• The 'mace' structure, resembling a Greek key-like motif, prevents further fibril elongation.

Conclusions:

• Heme acts as a modulator, transforming toxic α-Syn oligomers into a stable, less harmful state.
• Blocking the inter-protofilament His50 residue with heme offers a novel strategy for Parkinson's disease intervention.
• This study provides insights into α-Syn structure-toxicity relationships and potential therapeutic avenues.