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Quantitative interaction proteomics of neurodegenerative disease proteins

Hosp, Fabian, Vossfeldt, Hannes, Heinig, Matthias, Vasiljevic, Djordje, Arumughan, Anup, Wyler, Emanuel, Landthaler, Markus, Hubner, Norbert, Wanker, Erich E., Lannfelt, Lars, Ingelsson, Martin, Lalowski, Maciej, Voigt, Aaron, Selbach, Matthias, Owen, Michael John ORCID:, O'Donovan, Michael Conlon ORCID:, Escott-Price, Valentina ORCID:, Holmans, Peter Alan ORCID:, Williams, Julie ORCID: and Hamshere, Marian L. ORCID: 2015. Quantitative interaction proteomics of neurodegenerative disease proteins. Cell Reports 11 (7) , pp. 1134-46. 10.1016/j.celrep.2015.04.030

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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 A

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 2211-1247
Date of Acceptance: 14 April 2015
Last Modified: 31 Oct 2022 09:22

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