Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner.
Artikel i vetenskaplig tidskrift, 2015

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.

methods

chemistry

Protein Multimerization

chemistry

chemistry

chemistry

Atomic Force

Calorimetry

Thiazoles

alpha-Synuclein

Amyloid

Insulysin

Microscopy

Författare

Sandeep K Sharma

Umeå universitet

E. Chorell

Umeå universitet

Pär Steneberg

Umeå universitet

Emma Vernersson-Lindahl

Umeå universitet

Helena Edlund

Umeå universitet

Pernilla Wittung Stafshede

Umeå universitet

Scientific Reports

2045-2322 (ISSN)

Vol. 5 12531-

Ämneskategorier

Biokemi och molekylärbiologi

Biologiska vetenskaper

Biofysik

DOI

10.1038/srep12531

PubMed

26228656

Mer information

Senast uppdaterat

2019-06-12