Insulin-degrading enzyme prevents ?-synuclein fibril formation in a nonproteolytical manner.

ABSTRACT: The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid ? (??) 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 ?? and ?-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-?-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits ?-synuclein fibril formation by binding to ?-synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of ?-synuclein concentrations, interaction with ?-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-?-synuclein interactions, i.e. protection against ?-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo.

SUBMITTER: Sharma SK 

PROVIDER: S-EPMC4521159 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature