Cell reports (Cambridge), 2015-05-19, Vol.11 (7), p.1134-1146
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.
•Quantitative interactomics of proteins involved in four neurodegenerative diseases•Differential interaction mapping of wild-type and disease-associated proteins•Interaction partners are significantly linked to disease phenotypes in vivo•Interaction of APP and LRPPRC appears to induce mitochondrial dysfunction in AD
Hosp et al. show that quantitative interaction proteomics of neurodegenerative disease proteins captures interactions relevant to pathogenesis. Differential interactome mapping reveals preferential binding of the mitochondrial protein LRPPRC with an early-onset Alzheimer’s disease (AD) variant of APP, potentially contributing to mitochondrial dysfunction observed in AD.
Animals ; Chromatography, Liquid ; Genome-Wide Association Study ; Humans ; Immunoprecipitation ; Medical and Health Sciences ; Medical Biotechnology ; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ; Medicin och hälsovetenskap ; Medicinsk bioteknologi ; Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ; Neurodegenerative Diseases - metabolism ; Phenotype ; Proteomics - methods ; Tandem Mass Spectrometry
Alma/SFX Local Collection
SWEPUB Freely available online
DOAJ Directory of Open Access Journals - Not for CDI Discovery
https://www.ncbi.nlm.nih.gov/pubmed/25959826$$D View this record in MEDLINE/PubMed
Permalink to record
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-256232$$DView record from Swedish Publication Index