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 |