Structure-Toxicity Relationship in Intermediate Fibrils from α-Synuclein Condensates.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Aberrant aggregation of alpha-synuclein (αS) into amyloid fibrils is a hallmark of neurodegenerative diseases like Parkinson's disease.
• The structural characteristics of mature αS amyloids are known, but transient aggregation intermediates remain poorly understood.

Purpose of the Study:

• To characterize the structure and properties of intermediate amyloid fibrils formed during αS aggregation.
• To compare these intermediates with mature amyloids and elucidate their role in cytotoxicity and membrane binding.

Main Methods:

• Solid-state nuclear magnetic resonance (ssNMR)
• Cryogenic electron microscopy (cryo-EM)
• Biophysical assays
• Incubation with neuronal cells
• Antibody characterization
• Designed mutants

Main Results:

• Transient amyloid intermediates of αS were characterized, forming during aggregation from liquid condensates to mature fibrils.
• These intermediates possess a small antiparallel β-sheet core and a disordered N-terminal region, mediating membrane binding and inducing significant cytotoxicity.
• Mature amyloids exhibit distinct properties: a rearranged core including the N-terminus, lower cytotoxicity, and reduced membrane interaction.

Conclusions:

• The study clarifies the structural and functional differences between αS amyloid intermediates and mature fibrils.
• Key structural elements responsible for the membrane interaction and cytotoxicity of intermediate species were identified.
• These findings provide insights into the mechanisms of αS-mediated neurotoxicity and potential therapeutic strategies for Parkinson's disease.