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      The H50Q Mutation Induces a 10-fold Decrease in the Solubility of α-Synuclein*

      research-article
      , § ,   , , , ** ,   , , , ‡‡ , ‡‡ , , ** , §§ , ** , , §§ , , 1 , § , , ** , 3
      The Journal of Biological Chemistry
      American Society for Biochemistry and Molecular Biology
      alpha-Synuclein (a-synuclein), Amyloid, Fibril, Parkinson Disease, Protein Aggregation, Aggregation Propensity, Fibrils Thermodynamic Stability, Polyproline II Structure

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          Abstract

          Background: The basis of the pathogenicity of the H50Q variant α-synuclein is unknown.

          Results: The critical concentration of α-synuclein is decreased by 10-fold by the H50Q mutation, and its aggregation is modulated by the wild-type isoform.

          Conclusion: Key effects of the H50Q mutation on the aggregation of α-synuclein can be quantified.

          Significance: Our data provide insights into the mechanism of Lewy body formation in vivo.

          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.

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          Most cited references62

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          NMRPipe: a multidimensional spectral processing system based on UNIX pipes.

          The NMRPipe system is a UNIX software environment of processing, graphics, and analysis tools designed to meet current routine and research-oriented multidimensional processing requirements, and to anticipate and accommodate future demands and developments. The system is based on UNIX pipes, which allow programs running simultaneously to exchange streams of data under user control. In an NMRPipe processing scheme, a stream of spectral data flows through a pipeline of processing programs, each of which performs one component of the overall scheme, such as Fourier transformation or linear prediction. Complete multidimensional processing schemes are constructed as simple UNIX shell scripts. The processing modules themselves maintain and exploit accurate records of data sizes, detection modes, and calibration information in all dimensions, so that schemes can be constructed without the need to explicitly define or anticipate data sizes or storage details of real and imaginary channels during processing. The asynchronous pipeline scheme provides other substantial advantages, including high flexibility, favorable processing speeds, choice of both all-in-memory and disk-bound processing, easy adaptation to different data formats, simpler software development and maintenance, and the ability to distribute processing tasks on multi-CPU computers and computer networks.
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            Alpha-synuclein in Lewy bodies.

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              Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

              Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (9650 Rockville Pike, Bethesda, MD 20814, U.S.A. )
                0021-9258
                1083-351X
                23 January 2015
                10 December 2014
                10 December 2014
                : 290
                : 4
                : 2395-2404
                Affiliations
                From the []Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, and
                the [§ ]Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PF, United Kingdom,
                the []Centre for Genomic Regulation and University Pompeu Fabra, 08003 Barcelona, Spain,
                the [** ]Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy,
                the []Department of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom,
                the [§§ ]Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom, and
                the [‡‡ ]Department of Physics, University of Genoa, 16146 Genoa, Italy
                Author notes
                [1 ] To whom correspondence may be addressed: Dept. of Structural and Molecular Biology, University College London, WC1E 6BT London, UK. Tel.: 44-20-7679-2375; E-mail: j.christodoulou@ 123456ucl.ac.uk .
                [3 ] To whom correspondence may be addressed: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Div. of Medicine, University College London, Rowland Hill St., London NW3 2PF, UK. Tel.: 44-20-7433-2773; Fax: 44-20-7433-2803; E-mail: v.bellotti@ 123456ucl.ac.uk .
                [2]

                National Institute for Health Research Senior Investigator.

                Article
                M114.610527
                10.1074/jbc.M114.610527
                4303689
                25505181
                f48edc87-8686-43d3-8782-8ffefc286d2d
                © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version full access.

                Creative Commons Attribution Unported License applies to Author Choice Articles

                History
                : 14 September 2014
                : 25 November 2014
                Categories
                Molecular Bases of Disease

                Biochemistry
                alpha-synuclein (a-synuclein),amyloid,fibril,parkinson disease,protein aggregation,aggregation propensity,fibrils thermodynamic stability,polyproline ii structure

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