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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / physiopathology*
  • Brain Mapping / methods*
  • Humans
  • Neurodegenerative Diseases / genetics*
  • Protein Aggregates / genetics*
  • Protein Interaction Mapping / methods*


  • Protein Aggregates