The H50Q mutation induces a 10-fold decrease in the solubility of α-synuclein.

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Parkinson disease is characterized by Lewy bodies, primarily composed of aggregated alpha-synuclein (α-synuclein).
• Familial Parkinson disease mutations in α-synuclein offer insights into aggregation mechanisms.
• A novel pathogenic mutation, H50Q, exhibits accelerated aggregation compared to wild-type α-synuclein.

Purpose of the Study:

• To investigate the aggregation propensity of the α-synuclein H50Q mutation.
• To elucidate the structural and thermodynamic factors influencing H50Q-mediated aggregation.
• To explore the interaction between wild-type and mutant α-synuclein in aggregation.

Main Methods:

• Sequence-based prediction algorithm for aggregation propensity.
• NMR chemical shift analysis to determine monomeric secondary structure populations.
• Thermodynamic stability measurements of α-synuclein fibrils.

Main Results:

• The H50Q mutation causes minor changes in monomeric structure but significantly stabilizes α-synuclein fibrils (5.0 ± 1.0 kJ mol⁻¹).
• This stabilization increases monomeric α-synuclein supersaturation, favoring aggregation.
• Wild-type α-synuclein dose-dependently decelerates H50Q variant aggregation kinetics.

Conclusions:

• The H50Q mutation enhances α-synuclein aggregation primarily by stabilizing fibrils.
• The balance between wild-type and mutant α-synuclein alleles may influence Parkinson disease progression and clinical presentation.
• Understanding these interactions is crucial for developing targeted Parkinson disease therapies.