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

Sandeep K Sharma,Erik Chorell,Emma Vernersson-Lindahl,Helena Edlund,Pernilla Wittung-Stafshede,Pär Steneberg

doi:10.1038/srep12531

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.

Highlights

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
Accumulating data suggest that type 2 diabetes (T2D) and Alzheimer’s disease (AD) are associated and both diseases share the pathological characteristic of amyloid deposits, derived primarily from Islet Amyloid Polypeptide (IAPP) in T2D β -cells and Amyloid β (Α β ) in AD neurons[1,2,3,4]
Addition of Insulin-degrading enzyme (IDE) efficiently blocked the formation of α -synuclein amyloid fibers, as evident from IDE-concentration dependent decreases in thioflavin T (ThT) emission (Fig. 1A)

Summary

Introduction

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. 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. In addition to the proteolytical role for IDE in neutralizing amyloidogenic peptides an unexpected property to form a stable complex with both Α β and α -synuclein was recently shown in vitro and a protective ‘dead-end chaperone’ function was proposed for IDE11,13,14. We recently showed that, similar to what has been reported for Aβ 13,14, IDE formed SDS resistant complexes with α -synuclein in vitro[11]

Methods

Results

Conclusion