Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins
Fabian Hosp,
Hannes Vossfeldt,
Matthias Heinig,
Djordje Vasiljevic,
Anup Arumughan,
Emanuel Wyler,
Markus Landthaler,
Norbert Hubner,
Erich E. Wanker,
Lars Lannfelt,
Martin Ingelsson,
Maciej Lalowski,
Aaron Voigt,
Matthias Selbach
Affiliations
Fabian Hosp
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Hannes Vossfeldt
University Medical Center, RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
Matthias Heinig
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Djordje Vasiljevic
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Anup Arumughan
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Emanuel Wyler
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Markus Landthaler
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Norbert Hubner
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Erich E. Wanker
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
Lars Lannfelt
Uppsala University, Department of Public Health and Geriatrics, Uppsala University Hospital, Box, 609, 751 25 Uppsala, Sweden
Martin Ingelsson
Uppsala University, Department of Public Health and Geriatrics, Uppsala University Hospital, Box, 609, 751 25 Uppsala, Sweden
Maciej Lalowski
Biomedicum Helsinki, Meilahti Clinical Proteomics Core Facility and Folkhälsan Research Center, University of Helsinki, PO Box 63, Haartmaninkatu 8, Helsinki 00014, Finland
Aaron Voigt
University Medical Center, RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
Matthias Selbach
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
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.
