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The H50Q Mutation Induces a 10-fold Decrease in the Solubility of α-Synuclein
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DOI：10.1074/jbc.M114.610527.png)
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Abstract
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The conversion of alpha-synuclein from its intrinsically disordered monomeric state into the fibrillar cross-beta aggregates characteristically present in Lewy bodies is largely unknown. The investigation of alpha-synuclein variants causative of familial forms of Parkinson disease can provide unique insights into the conditions that promote or inhibit aggregate formation. It has been shown recently that a newly identified pathogenic mutation of alpha-synuclein, H50Q, aggregates faster than the wild-type. We investigate here its aggregation propensity by using a sequence-based prediction algorithm, NMRchemical shift analysis of secondary structure populations in the monomeric state, and determination of thermodynamic stability of the fibrils. Our data show that the H50Q mutation induces only a small increment in polyproline II structure around the site of the mutation and a slight increase in the overall aggregation propensity. We also find, however, that the H50Q mutation strongly stabilizes alpha-synuclein fibrils by 5.0 +/- 1.0 kJ mol(-1), thus increasing the supersaturation of monomeric alpha-synuclein within the cell, and strongly favors its aggregation process. We further show that wild-type alpha-synuclein can decelerate the aggregation kinetics of the H50Q variant in a dose-dependent manner when coaggregating with it. These last findings suggest that the precise balance of alpha-synuclein synthesized from the wild-type and mutant alleles may influence the natural history and heterogeneous clinical phenotype of Parkinson disease.
Keywords:
PARKINSONS-DISEASE
NEURODEGENERATIVE DISEASES
SECONDARY STRUCTURE
AGGREGATION RATES
AMYLOID FIBRILS
GLOBULAR-PROTEINS
LEWY BODIES
IN-VITRO
NMR
PREDICTION
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