Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms.

Autor: Andrew RJ; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK., Fisher K; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK., Heesom KJ; Proteomics Facility, Faculty of Medical and Veterinary Sciences, University of Bristol, Bristol, UK., Kellett KAB; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK., Hooper NM; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2019 May; Vol. 149 (3), pp. 399-412. Date of Electronic Publication: 2019 Feb 14.
DOI: 10.1111/jnc.14666
Abstrakt: The generation of the amyloid-β (Aβ) peptides from the amyloid precursor protein (APP) through sequential proteolysis by β- and γ-secretases is a key pathological event in the initiation and propagation of Alzheimer's disease. Aβ and the transcriptionally active APP intracellular domain are generated preferentially from the APP695 isoform compared to the longer APP751 isoform. As the Aβ and amyloid precursor protein intracellular domain produced from cleavage of APP695 and APP751 are identical we hypothesised that the two isoforms have differences within their interactomes which mediate the differential processing of the two isoforms. To investigate this, we applied a proteomics-based approach to identify differences in the interactomes of the APP695 and APP751 isoforms. Using stable isotope labelling of amino acids in cell culture and quantitative proteomics, we compared the interactomes of APP695 and APP751 expressed in human SH-SY5Y cells. Through this approach, we identified enrichment of proteins involved in mitochondrial function, the nuclear pore and nuclear transport specifically in the APP695 interactome. Further interrogation of the APP interactome and subsequent experimental validation (co-immunoprecipitation and siRNA knockdown) revealed GAP43 as a specific modulator of APP751 proteolysis, altering Aβ generation. Our data indicate that interrogation of the APP interactome can be exploited to identify proteins which influence APP proteolysis and Aβ production in an isoform dependent-manner. Cover Image for this issue: doi: 10.1111/jnc.14504.
(© 2019 International Society for Neurochemistry.)
Databáze: MEDLINE
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