Alpha-Synuclein Fibril Structures Cluster into Distinct Classes

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alpha-synuclein (Asyn) fibril accumulation defines Parkinson Disease (PD), Lewy Body Dementia (LBD), and Multiple System Atrophy (MSA).
• High-resolution Asyn fibril structures are essential for developing specific diagnostic and therapeutic agents.
• Existing structural data reveal significant polymorphism among Asyn fibrils.

Purpose of the Study:

• To objectively classify the diverse high-resolution structures of Alpha-synuclein fibrils.
• To identify conserved structural motifs within different fibril polymorphs.
• To assess the potential of these motifs as targets for drug development and disease modeling.

Main Methods:

• Utilized standard alignment tools and density-based clustering approaches to classify Asyn fibril structures.
• Analyzed approximately one hundred solid-state NMR (SSNMR) and cryo-electron microscopy (cryo-EM) structures from the Protein Data Bank (PDB).
• Examined conserved structural motifs and their implications for drug design and disease pathogenesis.

Main Results:

• 81% of analyzed Asyn fibril structures were objectively classified into two major polymorph classes.
• Identified subtle, conserved variations within each class, positioning sidechains as potential druggable targets.
• Found that conserved motifs associated with each class are present in nearly all published Asyn fibril structures.

Conclusions:

• The classification of Asyn fibril structures reveals two dominant polymorph classes with conserved motifs.
• These conserved motifs represent promising targets for designing highly specific ligands for clinical applications.
• In vitro fibrils serve as valuable substrates for drug development and models for neurodegenerative disease pathogenesis.