TY - JOUR
T1 - Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains
AU - Haenig, Christian
AU - Atias, Nir
AU - Taylor, Alexander K.
AU - Mazza, Arnon
AU - Schaefer, Martin H.
AU - Russ, Jenny
AU - Riechers, Sean Patrick
AU - Jain, Shushant
AU - Coughlin, Maura
AU - Fontaine, Jean Fred
AU - Freibaum, Brian D.
AU - Brusendorf, Lydia
AU - Zenkner, Martina
AU - Porras, Pablo
AU - Stroedicke, Martin
AU - Schnoegl, Sigrid
AU - Arnsburg, Kristin
AU - Boeddrich, Annett
AU - Pigazzini, Lucia
AU - Heutink, Peter
AU - Taylor, J. Paul
AU - Kirstein, Janine
AU - Andrade-Navarro, Miguel A.
AU - Sharan, Roded
AU - Wanker, Erich E.
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2020/8/18
Y1 - 2020/8/18
N2 - 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.
AB - 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.
KW - ARF-GEP
KW - PPI validation
KW - TDP-43
KW - aggregation modulators
KW - disease network modules
KW - disease-causing proteins
KW - neurodegenerative diseases
KW - protein aggregation
KW - protein-protein interactions
KW - yeast-two-hybrid
UR - http://www.scopus.com/inward/record.url?scp=85089435094&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.108050
DO - 10.1016/j.celrep.2020.108050
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C2 - 32814053
AN - SCOPUS:85089435094
SN - 2211-1247
VL - 32
JO - Cell Reports
JF - Cell Reports
IS - 7
M1 - 108050
ER -