Overexpression of calsenilin enhances gamma-secretase activity.
Presenilin/gamma-secretase is a membrane-associated protease that cleaves within the transmembrane region of the amyloid precursor protein (APP) to generate amyloid-beta peptide (Abeta) whose deposition in the brain is a characteristic of Alzheimer's disease (AD). Calsenilin, a calcium binding protein that has been shown to interact with the C-termini of both presenilin 1 (PS1) and presenilin 2 (PS2), appears to play a role in transcriptional regulation and apoptosis and to bind to A-type voltage-gated potassium channels. Here, we report that overexpression of calsenilin enhanced gamma-secretase activity in cells. The effect of calsenilin on the gamma-cleavage of substrates was blocked by the selective gamma-secretase inhibitor L-685,458. We also employed a cellular gamma-cleavage GFP-reporter assay to demonstrate the effect of calsenilin on gamma-secretase activity. To establish a direct role for calsenilin in regulating gamma-secretase activity, we incubated purified calsenilin with isolated membrane fractions and found increased Abeta production in a cell free system. These data suggest that calsenilin may be one of the regulatory factors for gamma-secretase.
Jo
Dong-Gyu
DG
Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Korea.
Jang
Jiyeon
J
Kim
Byung-Ju
BJ
Lundkvist
Johan
J
Jung
Yong-Keun
YK
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D002474:Cell-Free System; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D051605:Kv Channel-Interacting Proteins; D012097:Repressor Proteins / Q000096:biosynthesis*; D014162:Transfection
D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human