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

Porcari, R; Proukakis, C; Waudby, CA; Bolognesi, B; Mangione, PP; Paton, JF; Mullin, S; ... Bellotti, V; + view all (2015) The H50Q mutation induces a 10-fold decrease in the solubility of α-synuclein. J Biol Chem , 290 (4) 2395 - 2404. 10.1074/jbc.M114.610527. Green open access

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Abstract

The conversion of α-synuclein from its intrinsically disordered monomeric state into the fibrillar cross-β aggregates characteristically present in Lewy bodies is largely unknown. The investigation of α-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 α-synuclein, H50Q, aggregates faster than the wild-type. We investigate here its aggregation propensity by using a sequence-based prediction algorithm, NMR chemical 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 α-synuclein fibrils by 5.0 ± 1.0 kJ mol(-1), thus increasing the supersaturation of monomeric α-synuclein within the cell, and strongly favors its aggregation process. We further show that wild-type α-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 α-synuclein synthesized from the wild-type and mutant alleles may influence the natural history and heterogeneous clinical phenotype of Parkinson disease.

Type: Article
Title: The H50Q mutation induces a 10-fold decrease in the solubility of α-synuclein
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M114.610527
Publisher version: http://dx.doi.org/10.1074/jbc.M114.610527
Language: English
Additional information: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Creative Commons Attribution Unported License applies to Author Choice Articles.
Keywords: Aggregation Propensity, Amyloid, Fibril, Fibrils Thermodynamic Stability, Parkinson Disease, Polyproline II Structure, Protein Aggregation, alpha-Synuclein (a-synuclein), Amyloid, Binding Sites, Humans, Lewy Bodies, Magnetic Resonance Spectroscopy, Microscopy, Atomic Force, Mutation, Parkinson Disease, Peptides, Phenotype, Protein Binding, Protein Isoforms, Protein Structure, Secondary, Recombinant Proteins, Solubility, Thermodynamics, alpha-Synuclein
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/1458760
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