Quantitative interaction proteomics of neurodegenerative disease proteins.

Abstract

Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

• Authors: Fabian Hosp, Hannes Vossfeldt, Matthias Heinig, Djordje Vasiljevic, Anup Arumughan, Emanuel Wyler, Genetic and Environmental Risk for Alzheimer’s Disease GERAD1 Consortium, Markus Landthaler, Norbert Hubner, Erich E Wanker, Lars Lannfelt, Martin Ingelsson, Maciej Lalowski, Aaron Voigt, Matthias Selbach
• Journal: Cell reports (Cell Rep) Vol. 11 Issue 7 Pg. 1134-46 (May 19 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 25959826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Topics

• Animals
• Chromatography, Liquid
• Genome-Wide Association Study
• Humans
• Immunoprecipitation
• Neurodegenerative Diseases (metabolism)
• Phenotype
• Proteomics (methods)
• Tandem Mass Spectrometry