Fibril fuzzy coat is important for α-synuclein pathological transmission activity

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Alpha-synuclein (α-synuclein) transmission and propagation are key features of synucleinopathies.
• The precise molecular mechanisms governing this pathological process are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying α-synuclein transmission and propagation.
• To identify factors influencing neuronal seeding activity and fibril aggregation.

Main Methods:

• Utilized α-synuclein preformed fibrils as pathological seeds for serial propagation experiments.
• Employed cryoelectron microscopy (Cryo-EM) and solid-state nuclear magnetic resonance (ssNMR) to analyze fibril structures.
• Applied hydrogen/deuterium exchange mass spectrometry (HDX-MS) to study fibril dynamics.
• Developed a mini-P-selective antibody to identify active fibril types in human samples.

Main Results:

• Observed a decline in neuronal transmission activity during serial propagation of α-synuclein fibrils.
• Identified two fibril polymorphisms, mini-P (high seeding activity) and mini-S (accelerated aggregation), with differing proportions over time.
• Cryo-EM and ssNMR revealed similar fibril cores but distinct "fuzzy coat" flexibilities between mini-P and mini-S.
• HDX-MS supported a model where fuzzy coat-core interactions critically impact neuronal transmission.
• Detected active fibril types in human synucleinopathy brain regions using the mini-P-selective antibody.

Conclusions:

• The "fuzzy coat" of α-synuclein fibrils plays a crucial role in pathological protein transmission.
• Fibril polymorphism and the dynamics of the fuzzy coat significantly influence disease propagation.
• The fuzzy coat represents a potential therapeutic target for treating synucleinopathies.