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Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 12531Article in journal (Refereed) Published
Abstract [en]

The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Aβ) and Islet Amyloid Polypeptide (IAPP), i.e. peptides associated with Alzheimer's disease and type 2 diabetes, respectively. In addition to the protease activity normally associated with IDE function an additional activity involving the formation of stable, irreversible complexes with both Aβ and α-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-α-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits α-synuclein fibril formation by binding to α-synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of α-synuclein concentrations, interaction with α-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-α-synuclein interactions, i.e. protection against α-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015. Vol. 5, 12531
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Neurosciences
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URN: urn:nbn:se:umu:diva-107289DOI: 10.1038/srep12531ISI: 000358773300001PubMedID: 26228656OAI: oai:DiVA.org:umu-107289DiVA: diva2:849783
Available from: 2015-08-31 Created: 2015-08-21 Last updated: 2017-12-04Bibliographically approved

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Sharma, Sandeep KChorell, ErikSteneberg, PärVernersson-Lindahl, EmmaEdlund, HelenaWittung-Stafshede, Pernilla
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