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Quantitative interaction proteomics of neurodegenerative disease proteins

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Item Type:Article
Title:Quantitative interaction proteomics of neurodegenerative disease proteins
Creators Name:Hosp, F. and Vossfeldt, H. and Heinig, M. and Vasiljevic, D. and Arumughan, A. and Wyler, E. and Landthaler, M. and Hubner, N. and Wanker, E.E. and Lannfelt, L. and Ingelsson, M. and Lalowski, M. and Voigt, A. and Selbach, M.
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.
Keywords:Genome-Wide Association Study, Immunoprecipitation, Liquid Chromatography, Neurodegenerative Diseases, Phenotype, Proteomics, Tandem Mass Spectrometry, Animals
Source:Cell Reports
Publisher:Cell Press / Elsevier
Page Range:1134-1146
Date:19 May 2015
Official Publication:https://doi.org/10.1016/j.celrep.2015.04.030
PubMed:View item in PubMed

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