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Titolo:
The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein
Autore:
Cupers, P; Bentahir, M; Craessaerts, K; Orlans, I; Vanderstichele, H; Saftig, P; De Strooper, B; Annaert, W;
Indirizzi:
Flanders Interuniv Inst Biotechnol, Ctr Human Genet, Neuronal Cell Biol Grp, B-3000 Leuven, Belgium Flanders Interuniv Inst Biotechnol Leuven Belgium B-3000 Leuven, Belgium Katholieke Univ Leuven, B-3000 Leuven, Belgium Katholieke Univ Leuven Leuven Belgium B-3000 ven, B-3000 Leuven, Belgium Univ Gottingen, Dept Biochem 2, D-37073 Gottingen, Germany Univ GottingenGottingen Germany D-37073 m 2, D-37073 Gottingen, Germany Innogenet NV, B-9052 Ghent, Belgium Innogenet NV Ghent Belgium B-9052Innogenet NV, B-9052 Ghent, Belgium
Titolo Testata:
JOURNAL OF CELL BIOLOGY
fascicolo: 4, volume: 154, anno: 2001,
pagine: 731 - 740
SICI:
0021-9525(20010820)154:4<731:TDBPSL>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
ALZHEIMERS-DISEASE; ENDOPLASMIC-RETICULUM; HIPPOCAMPAL-NEURONS; DISINTEGRIN-METALLOPROTEASE; INTERMEDIATE COMPARTMENT; TRANSMEMBRANE PROTEINS; SIGNAL-TRANSDUCTION; CEREBROSPINAL-FLUID; MEMBRANE-PROTEIN; NT2N CELLS;
Keywords:
presenilin 1; amyloid peptide; gamma-secretase; ER retention; APP processing;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
57
Recensione:
Indirizzi per estratti:
Indirizzo: Annaert, W Flanders Interuniv Inst Biotechnol, Ctr Human Genet, Neuronal Cell Biol Grp, Herestr 49, B-3000 Leuven, Belgium Flanders Interuniv Inst Biotechnol Herestr 49 Leuven Belgium B-3000
Citazione:
P. Cupers et al., "The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein", J CELL BIOL, 154(4), 2001, pp. 731-740

Abstract

We investigated the relationship between PSI and gamma -secretase processing of amyloid precursor protein (APP) in primary cultures of neurons. Increasing the amount of APP at the cell surface or towards endosomes did not significantly affect PS1-dependent gamma -secretase cleavage, although littlePS1 is present in those subcellular compartments. In contrast, almost no gamma -secretase processing was observed when holo-APP or APP-C99, a direct substrate for gamma -secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif. Nevertheless, APP-C99-dilysine (KK) colocalized with PS1 in the ER. In contrast, APP-C99 did notcolocalize with PS1, but was efficiently processed by PS1-dependent gamma -secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that gamma -secretase cleavage of APP-C99 occurs in a specialized subcellular compartment where little or no PS1 is detected. This suggests that at least one other factor than PS1, located downstream of the ER, is required for the gamma -cleavage of APP-C99. In agreement, we found that intracellular gamma -secretase processing of APP-C99-KK both at the gamma 40 and the gamma 42 site could be restored partially after brefeldin A treatment. Our data confirm the "spatial paradox" and raise several questions regarding the PS1 is gamma -secretase hypothesis.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 00:08:57