title: 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.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hosp
authors.affiliation: University Medical Center, RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Vossfeldt
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany; Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Djordje
authors.initials: D
authors.lastname: Vasiljevic
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Anup
authors.initials: A
authors.lastname: Arumughan
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Wyler
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Landthaler
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.affiliation: Uppsala University, Department of Public Health and Geriatrics, Uppsala University Hospital, Box, 609, 751 25 Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.affiliation: Uppsala University, Department of Public Health and Geriatrics, Uppsala University Hospital, Box, 609, 751 25 Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.affiliation: Biomedicum Helsinki, Meilahti Clinical Proteomics Core Facility and Folkhälsan Research Center, University of Helsinki, PO Box 63, Haartmaninkatu 8, Helsinki 00014, Finland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lalowski
authors.affiliation: University Medical Center, RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.
authors.forename: Aaron
authors.initials: A
authors.lastname: Voigt
authors.affiliation: Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany. Electronic address: matthias.selbach@mdc-berlin.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Selbach
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D055106:Genome-Wide Association Study; D006801:Humans; D047468:Immunoprecipitation; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010641:Phenotype; D040901:Proteomics / Q000379:methods*; D053719:Tandem Mass Spectrometry