Quantitative interaction proteomics of neurodegenerative disease proteins

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, Patrick Kehoe

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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.

Original languageEnglish
Pages (from-to)1134-1146
Number of pages13
JournalCell Reports
Volume11
Issue number7
Early online date7 May 2015
DOIs
Publication statusPublished - 19 May 2015

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    Hosp, F., Vossfeldt, H., Heinig, M., Vasiljevic, D., Arumughan, A., Wyler, E., Genetic and Environmental Risk for Alzheimer's Disease (GERAD1) Consortium, Landthaler, M., Hubner, N., Wanker, E. E., Lannfelt, L., Ingelsson, M., Lalowski, M., Voigt, A., Selbach, M., & Kehoe, P. (2015). Quantitative interaction proteomics of neurodegenerative disease proteins. Cell Reports, 11(7), 1134-1146. https://doi.org/10.1016/j.celrep.2015.04.030