Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains

Cell Rep. 2020 Aug 18;32(7):108050. doi: 10.1016/j.celrep.2020.108050.

Christian Haenig ¹, Nir Atias ², Alexander K Taylor ³, Arnon Mazza ², Martin H Schaefer ⁴, Jenny Russ ¹, Sean-Patrick Riechers ¹, Shushant Jain ⁵, Maura Coughlin ³, Jean-Fred Fontaine ⁶, Brian D Freibaum ³, Lydia Brusendorf ¹, Martina Zenkner ¹, Pablo Porras ⁷, Martin Stroedicke ¹, Sigrid Schnoegl ¹, Kristin Arnsburg ⁸, Annett Boeddrich ¹, Lucia Pigazzini ⁸, Peter Heutink ⁵, J Paul Taylor ⁹, Janine Kirstein ⁸, Miguel A Andrade-Navarro ⁶, Roded Sharan ¹⁰, Erich E Wanker ¹¹

Affiliations

1 Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
2 School of Computer Science, Tel-Aviv University, Tel-Aviv 69978, Israel.
3 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
4 Division of Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Computational Cancer Biology, European Institute of Oncology, 20141 Milano, Italy.
5 DZNE Tübingen and Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.
6 Division of Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Institute of Organismic and Molecular Evolution, Johannes Gutenberg University of Mainz, 55122 Mainz, Germany.
7 Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
8 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) im Forschungsverbund Berlin e.V., 13125 Berlin, Germany.
9 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA.
10 School of Computer Science, Tel-Aviv University, Tel-Aviv 69978, Israel. Electronic address: roded@tauex.tau.ac.il.
11 Neuroproteomics, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: erich.w@mdc-berlin.de.

PMID: 32814053 DOI: 10.1016/j.celrep.2020.108050

Abstract

Interactome maps are valuable resources to elucidate protein function and disease mechanisms. Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions. This network reveals interconnectivity across diseases and links many known ND-causing proteins, such as α-synuclein, TDP-43, and ATXN1, to a host of proteins previously unrelated to NDs. It facilitates the identification of interacting proteins that significantly influence mutant TDP-43 and HTT toxicity in transgenic flies, as well as of ARF-GEP₁₀₀ that controls misfolding and aggregation of multiple ND-causing proteins in experimental model systems. Furthermore, it enables the prediction of ND-specific subnetworks and the identification of proteins, such as ATXN1 and MKL1, that are abnormally aggregated in postmortem brains of Alzheimer's disease patients, suggesting widespread protein aggregation in NDs.

Keywords

ARF-GEP(100); PPI validation; TDP-43; aggregation modulators; disease network modules; disease-causing proteins; neurodegenerative diseases; protein aggregation; protein-protein interactions; yeast-two-hybrid.

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