Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins

the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1134-1146
Number of pages13
JournalCell Reports
Volume11
Issue number7
DOIs
StatePublished - May 19 2015

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Neurodegenerative diseases
Neurodegenerative Diseases
Proteomics
Alzheimer Disease
Amyloid beta-Protein Precursor
Presenilin-1
Spinocerebellar Ataxias
Phenotype
Proteins
Genome-Wide Association Study
Mitochondrial Proteins
Huntington Disease
Proteolysis
Parkinson Disease
Binders
Toxicity
Genes
Association reactions
Degradation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium (2015). Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins. Cell Reports, 11(7), 1134-1146. https://doi.org/10.1016/j.celrep.2015.04.030

Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins. / the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium.

In: Cell Reports, Vol. 11, No. 7, 19.05.2015, p. 1134-1146.

Research output: Contribution to journalArticle

the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium 2015, 'Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins', Cell Reports, vol. 11, no. 7, pp. 1134-1146. https://doi.org/10.1016/j.celrep.2015.04.030
the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium. Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins. Cell Reports. 2015 May 19;11(7):1134-1146. https://doi.org/10.1016/j.celrep.2015.04.030
the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium. / Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins. In: Cell Reports. 2015 ; Vol. 11, No. 7. pp. 1134-1146.
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abstract = "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.",
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AU - Russo, Giancarlo

AU - Hamshere, Marian

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AU - Dowzell, Kimberley

AU - Williams, Amy

AU - Jones, Nicola

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AU - Morgan, Angharad

AU - Lovestone, Simon

AU - Powell, John

AU - Proitsi, Petroula

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AU - Brayne, Carol

AU - Rubinsztein, David C.

AU - Gill, Michael

AU - Lawlor, Brian

AU - Lynch, Aoibhinn

AU - Morgan, Kevin

AU - Brown, Kristelle

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AU - Craig, David

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Johnston, Janet

AU - Holmes, Clive

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AU - Younkin, Steven G

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