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Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity

Kruppa, AJ; Ott, S; Chandraratna, DS; Irving, JA; Page, RM; Speretta, E; Seto, T; ... Crowther, DC; + view all (2013) Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease , 1832 (12) 2115 - 2126. 10.1016/j.bbadis.2013.07.019. Green open access

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Abstract

The accumulation of β-amyloid (Aβ) peptide in the brain is one of the pathological hallmarks of Alzheimer's disease and is thought to be of primary aetiological significance. In an unbiased genetic screen, we identified puromycin-sensitive aminopeptidase (PSA) as a potent suppressor of Aβ toxicity in a Drosophila model system. We established that coexpression of Drosophila PSA (dPSA) in the flies' brains improved their lifespan, protected against locomotor deficits, and reduced brain Aβ levels by clearing the Aβ plaque-like deposits. However, confocal microscopy and subcellular fractionation of amyloid-expressing 7PA2 cells demonstrated that PSA localizes to the cytoplasm. Therefore, PSA and Aβ are unlikely to be in the same cellular compartment; moreover, when we artificially placed them in the same compartment in flies, we could not detect a direct epistatic interaction. The consequent hypothesis that PSA's suppression of Aβ toxicity is indirect was supported by the finding that Aβ is not a proteolytic substrate for PSA in vitro. Furthermore, we showed that the enzymatic activity of PSA is not required for rescuing Aβ toxicity in neuronal SH-SY5Y cells. We investigated whether the stimulation of autophagy by PSA was responsible for these protective effects. However PSA's promotion of autophagosome fusion with lysosomes required proteolytic activity and so its effect on autophagy is not identical to its protection against Aβ toxicity.

Type: Article
Title: Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbadis.2013.07.019
Publisher version: http://dx.doi.org/10.1016/j.bbadis.2013.07.019
Language: English
Additional information: © 2013 The Authors. Published by Elsevier B.V. Open Access funded by Wellcome Trust. Published under a Creative Commons license (http://creativecommons.org/licenses/by-nc-sa/3.0/).
Keywords: Alzheimer, Amyloid, Autophagy, Proteolysis, Puromycin-sensitive aminopeptidase, Alzheimer Disease, Aminopeptidases, Amyloid beta-Peptides, Animals, Animals, Genetically Modified, Autophagy, Blotting, Western, Brain, Drosophila melanogaster, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Neuroblastoma, Neurons, Proteolysis, Puromycin, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > VP: Health
URI: https://discovery.ucl.ac.uk/id/eprint/1405753
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