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

Christian Haenig, Nir Atias, Alexander K. Taylor, Arnon Mazza, Martin H. Schaefer, Jenny Russ, Sean Patrick Riechers, Shushant Jain, Maura Coughlin, Jean Fred Fontaine, Brian D. Freibaum, Lydia Brusendorf, Martina Zenkner, Pablo Porras, Martin Stroedicke, Sigrid Schnoegl, Kristin Arnsburg, Annett Boeddrich, Lucia Pigazzini, Peter HeutinkJ. Paul Taylor, Janine Kirstein, Miguel A. Andrade-Navarro, Roded Sharan, Erich E. Wanker

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number108050
JournalCell Reports
Volume32
Issue number7
DOIs
Publication statusPublished - Aug 18 2020

Keywords

  • aggregation modulators
  • ARF-GEP
  • disease network modules
  • disease-causing proteins
  • neurodegenerative diseases
  • PPI validation
  • protein aggregation
  • protein-protein interactions
  • TDP-43
  • yeast-two-hybrid

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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