The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure.

Area of Science:

• Neuroscience
• Structural Biology
• Biochemistry

Background:

• Alpha-synuclein (α-synuclein) aggregation is central to Parkinson's disease and related disorders.
• Hereditary mutations in α-synuclein, such as E46K, are linked to increased disease pathogenicity.
• Understanding mutation-induced structural changes in α-synuclein fibrils is crucial for disease mechanism insights.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils with the E46K mutation.
• To elucidate how the E46K mutation affects α-synuclein fibril structure and stability.
• To provide a structural basis for the enhanced pathogenicity of E46K mutant α-synuclein.

Main Methods:

• Cryo-electron microscopy (cryo-EM) at 2.5-Å resolution.
• Structural analysis of α-synuclein fibrils.
• Comparison of wild-type and E46K mutant α-synuclein fibril structures.

Main Results:

• The E46K mutation results in a rearranged, lower-energy fold of α-synuclein fibrils.
• The structure reveals a symmetric double protofilament conformation.
• The E46K mutation appears to avoid electrostatic repulsion, leading to a more stable fibril structure compared to wild-type.

Conclusions:

• The E46K mutation unlocks a more stable and pathogenic α-synuclein fibril structure.
• This structural change may explain the increased disease risk and severity in patients with the E46K mutation.
• The findings offer fundamental insights into α-synuclein biology and the structural basis of synucleinopathies.