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 Heutink; J. Paul Taylor; Janine Kirstein; Miguel A. Andrade-Navarro; Roded Sharan; Erich E. Wanker

doi:10.1016/j.celrep.2020.108050

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^*

^*Corresponding author for this work

School of Computer Science

Research output: Contribution to journal › Article › peer-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 language	English
Article number	108050
Journal	Cell Reports
Volume	32
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2020.108050
State	Published - 18 Aug 2020

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2020.108050

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Haenig, C., Atias, N., Taylor, A. K., Mazza, A., Schaefer, M. H., Russ, J., Riechers, S. P., Jain, S., Coughlin, M., Fontaine, J. F., Freibaum, B. D., Brusendorf, L., Zenkner, M., Porras, P., Stroedicke, M., Schnoegl, S., Arnsburg, K., Boeddrich, A., Pigazzini, L., ... Wanker, E. E. (2020). Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell Reports, 32(7), Article 108050. https://doi.org/10.1016/j.celrep.2020.108050

@article{dc227476c24f4c9885e84ab376a2194a,

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

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, PPI validation, TDP-43, aggregation modulators, disease network modules, disease-causing proteins, neurodegenerative diseases, protein aggregation, protein-protein interactions, yeast-two-hybrid",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = aug,

day = "18",

doi = "10.1016/j.celrep.2020.108050",

language = "אנגלית",

volume = "32",

journal = "Cell Reports",

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Haenig, C, Atias, N, Taylor, AK, Mazza, A, Schaefer, MH, Russ, J, Riechers, SP, Jain, S, Coughlin, M, Fontaine, JF, Freibaum, BD, Brusendorf, L, Zenkner, M, Porras, P, Stroedicke, M, Schnoegl, S, Arnsburg, K, Boeddrich, A, Pigazzini, L, Heutink, P, Taylor, JP, Kirstein, J, Andrade-Navarro, MA, Sharan, R & Wanker, EE 2020, 'Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains', Cell Reports, vol. 32, no. 7, 108050. https://doi.org/10.1016/j.celrep.2020.108050

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.

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

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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 -

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

Abstract

Keywords

UN SDGs

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