Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner
2015 (English)In: Scientific Reports, ISSN 2045-2322, Vol. 5, 12531Article in journal (Refereed) Published
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
IdentifiersURN: urn:nbn:se:umu:diva-107289DOI: 10.1038/srep12531ISI: 000358773300001PubMedID: 26228656OAI: oai:DiVA.org:umu-107289DiVA: diva2:849783