Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins

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

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


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
Pages (from-to)1134-1146
Number of pages13
JournalCell Reports
Issue number7
StatePublished - 19 May 2015
Externally publishedYes


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