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

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 toxic...

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Published in:Biochimica et biophysica acta 2013-12, Vol.1832 (12), p.2115-2126
Main Authors: Kruppa, Antonina J., Ott, Stanislav, Chandraratna, Dhia S., Irving, James A., Page, Richard M., Speretta, Elena, Seto, Tiffany, Camargo, Luiz Miguel, Marciniak, Stefan J., Lomas, David A., Crowther, Damian C.
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Language:English
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Summary: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. •PSA is a potent suppressor of Aβ toxicity and reduces brain Aβ levels in flies.•PSA is cytoplasmic but there is no direct epistatic interaction with Aβ in vivo.•Aβ is not a proteolytic substrate for PSA in vitro.•The enzymatic activity of PSA is not required for rescuing Aβ toxicity in cells.•PSA stimulates autophagy but this is unlikely to be the mechanism that suppresses Aβ toxicity.
ISSN:0925-4439
0006-3002
1879-260X
DOI:10.1016/j.bbadis.2013.07.019