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.
Bibliographical noteFunding Information:
We would like to thank Christian Sommer, Katja Neugebauer, and Teija Inkinen for excellent technical assistance and Kathrin Saar for help with the dbGaP access. We gratefully acknowledge the kind gift of the ATXN1 fly strains from the Juan Botas lab (Baylor College of Medicine). GWAS data acknowledgements can be found in the Supplemental Information . The research leading to these results has received funding from the NGNF-plus network NeuroNet (BMBF) and the Cross-Program Initiative Personalized Medicine (iMed) of the Helmholtz Association. Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s Disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortium provided data but did not participate in analysis or writing of this report. A full list of GERAD1 investigators can be found in the Supplemental Information .
© 2015 The Authors.
Copyright 2017 Elsevier B.V., All rights reserved.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)