title: Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner.
abstract: The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Αβ) 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 Αβ 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.
authors.affiliation: Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Chorell
authors.affiliation: Umeå Center for Molecular Medicine, Umeå University, 90187 Umeå, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Steneberg
authors.affiliation: Umeå Center for Molecular Medicine, Umeå University, 90187 Umeå, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Vernersson-Lindahl
authors.affiliation: Umeå Center for Molecular Medicine, Umeå University, 90187 Umeå, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Edlund
authors.affiliation: Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wittung-Stafshede
mesh_terms: D000682:Amyloid / Q000737:chemistry; D052160:Benzothiazoles; D002151:Calorimetry / Q000379:methods; D007339:Insulysin / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D055503:Protein Multimerization; D013844:Thiazoles / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; D007339:Insulysin