RRC ID 28073
著者 Kruppa AJ, Ott S, Chandraratna DS, Irving JA, Page RM, Speretta E, Seto T, Camargo LM, Marciniak SJ, Lomas DA, Crowther DC.
タイトル Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity.
ジャーナル Biochim Biophys Acta
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.
巻・号 1832(12)
ページ 2115-26
公開日 2013-12-1
DOI 10.1016/j.bbadis.2013.07.019
PII S0925-4439(13)00262-7
PMID 23911349
PMC PMC3898073
MeSH Alzheimer Disease / metabolism Alzheimer Disease / pathology Alzheimer Disease / prevention & control* Aminopeptidases / pharmacology* Amyloid beta-Peptides / adverse effects* Animals Animals, Genetically Modified Autophagy Blotting, Western Brain / metabolism* Drosophila melanogaster / genetics Drosophila melanogaster / growth & development Drosophila melanogaster / metabolism* Enzyme-Linked Immunosorbent Assay Flow Cytometry Fluorescent Antibody Technique Humans Immunoenzyme Techniques Neuroblastoma / metabolism Neuroblastoma / pathology Neuroblastoma / prevention & control* Neurons / drug effects Neurons / metabolism Neurons / pathology Proteolysis Puromycin / pharmacology RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured
IF 3.411
引用数 8
WOS 分野 BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
ショウジョウバエ 1009R-2 1009R-3