TY - JOUR
T1 - Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins
AU - the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium
AU - Hosp, Fabian
AU - Vossfeldt, Hannes
AU - Heinig, Matthias
AU - Vasiljevic, Djordje
AU - Arumughan, Anup
AU - Wyler, Emanuel
AU - Landthaler, Markus
AU - Hubner, Norbert
AU - Wanker, Erich E.
AU - Lannfelt, Lars
AU - Ingelsson, Martin
AU - Lalowski, Maciej
AU - Voigt, Aaron
AU - Selbach, Matthias
AU - Harold, Denise
AU - Abraham, Richard
AU - Hollingworth, Paul
AU - Sims, Rebecca
AU - Gerrish, Amy
AU - Chapman, Jade
AU - Russo, Giancarlo
AU - Hamshere, Marian
AU - Singh Pahwa, Jaspreet
AU - Escott-Price, Valentina
AU - Dowzell, Kimberley
AU - Williams, Amy
AU - Jones, Nicola
AU - Thomas, Charlene
AU - Stretton, Alexandra
AU - Morgan, Angharad
AU - Lovestone, Simon
AU - Powell, John
AU - Proitsi, Petroula
AU - Lupton, Michelle K.
AU - Brayne, Carol
AU - Rubinsztein, David C.
AU - Gill, Michael
AU - Lawlor, Brian
AU - Lynch, Aoibhinn
AU - Morgan, Kevin
AU - Brown, Kristelle
AU - Passmore, Peter
AU - Craig, David
AU - McGuinness, Bernadette
AU - Todd, Stephen
AU - Johnston, Janet
AU - Holmes, Clive
AU - Mann, David
AU - Cruchaga, Carlos
AU - Morris, John C.
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/5/19
Y1 - 2015/5/19
N2 - Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function isnot completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer’s disease (AD), Huntingtin (HTT) for Huntington’s disease, Parkin(PARK2) for Parkinson’s disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes invivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.
AB - Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function isnot completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer’s disease (AD), Huntingtin (HTT) for Huntington’s disease, Parkin(PARK2) for Parkinson’s disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes invivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.
UR - http://www.scopus.com/inward/record.url?scp=84929709547&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.04.030
DO - 10.1016/j.celrep.2015.04.030
M3 - Article
C2 - 25959826
AN - SCOPUS:84929709547
SN - 2211-1247
VL - 11
SP - 1134
EP - 1146
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -