TY - JOUR
T1 - Quantitative interaction proteomics of neurodegenerative disease proteins
AU - Hosp, Fabian
AU - Vossfeldt, Hannes
AU - Heinig, Matthias
AU - Vasiljevic, Djordje
AU - Arumughan, Anup
AU - Wyler, Emanuel
AU - Genetic and Environmental Risk for Alzheimer's Disease (GERAD1) Consortium
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 - Kehoe, Patrick
PY - 2015/5/19
Y1 - 2015/5/19
N2 - Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not 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 in vivo. 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 is not 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 in vivo. 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.
U2 - 10.1016/j.celrep.2015.04.030
DO - 10.1016/j.celrep.2015.04.030
M3 - Article (Academic Journal)
C2 - 25959826
SN - 2211-1247
VL - 11
SP - 1134
EP - 1146
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -