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Titolo:
Carboxyl-terminal fragments of Alzheimer beta-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
Autore:
Chen, FS; Yang, DS; Petanceska, S; Yang, A; Tandon, A; Yu, G; Rozmahel, R; Ghiso, J; Nishimura, M; Zhang, DM; Kawara, T; Levesque, G; Mills, J; Levesque, L; Song, YQ; Rogaeva, E; Westaway, D; Mount, H; Gandy, S; St George-Hyslop, P; Fraser, PE;
Indirizzi:
Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Lab Med & Pathobiol, Toronto, ON M5S 3H2, Canada Univ Toronto Toronto ON Canada M5S 3H2 obiol, Toronto, ON M5S 3H2, Canada Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Med Biophys, Toronto, ON M5S 3H2, Canada Univ Toronto Toronto ON Canada M5S 3H2 ophys, Toronto, ON M5S 3H2, Canada Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Med, Toronto, ON M5S 3H2, Canada Univ Toronto Toronto ON Canada M5S 3H2 t Med, Toronto, ON M5S 3H2, Canada Toronto Hosp, Dept Med Neurol, Toronto, ON M5S 3H2, Canada Toronto Hosp Toronto ON Canada M5S 3H2 eurol, Toronto, ON M5S 3H2, Canada NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Dept Psychiat, Orangeburg,NY 10962 USA NYU Orangeburg NY USA 10962 t Res, Dept Psychiat, Orangeburg,NY 10962 USA NYU, Sch Med, Nathan S Kline Inst Psychiat Res, Dept Pathol, Orangeburg, NY 10962 USA NYU Orangeburg NY USA 10962 at Res, Dept Pathol, Orangeburg, NY 10962 USA Hosp Sick Children, Res Inst, Dept Pharmacol, Toronto, ON M5S 3H2, Canada Hosp Sick Children Toronto ON Canada M5S 3H2 Toronto, ON M5S 3H2, Canada Hosp Sick Children, Res Inst, Dept Genet, Toronto, ON M5S 3H2, Canada HospSick Children Toronto ON Canada M5S 3H2 Toronto, ON M5S 3H2, Canada Hosp Sick Children, Dept Genet, Toronto, ON M5S 3H2, Canada Hosp Sick Children Toronto ON Canada M5S 3H2 Toronto, ON M5S 3H2, Canada Univ Toronto, Dept Pharmacol, Toronto, ON M5S 3H2, Canada Univ Toronto Toronto ON Canada M5S 3H2 macol, Toronto, ON M5S 3H2, Canada
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 47, volume: 275, anno: 2000,
pagine: 36794 - 36802
SICI:
0021-9258(20001124)275:47<36794:CFOABP>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
DISEASE-ASSOCIATED PRESENILINS; ENDOPLASMIC-RETICULUM; SECRETASE CLEAVAGE; GOLGI-COMPLEX; HIPPOCAMPAL-NEURONS; MISSENSE MUTATIONS; PEPTIDE VARIANTS; CULTURED-CELLS; PC12 CELLS; PRE-GOLGI;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
75
Recensione:
Indirizzi per estratti:
Indirizzo: St George-Hyslop, P Univ Toronto, Ctr Res Neurodegenerat Dis, Dept Lab Med& Pathobiol, 6 Queens Pk Crescent W, Toronto, ON M5S 3H2, Canada Univ Toronto 6 Queens Pk Crescent W Toronto ON Canada M5S 3H2
Citazione:
F.S. Chen et al., "Carboxyl-terminal fragments of Alzheimer beta-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells", J BIOL CHEM, 275(47), 2000, pp. 36794-36802

Abstract

Absence of functional presenilin 1 (PS1) protein leads to loss of gamma -secretase cleavage of the amyloid precursor protein (beta APP), resulting ina dramatic reduction in amyloid beta peptide (A beta) production and accumulation of alpha- or beta -secretase-cleaved COOH-terminal fragments of PAPP (alpha- or beta -CTFs). The major COOH-terminal fragment (CTF) in brain was identified as PAPP-CTF-(11-98), which is consistent with the observationthat cultured neurons generate primarily A beta-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length beta APP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1-/- neurons lasin normal cells) trafficking of beta APP to the Golgi compartment is necessary before alpha- and beta -secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual gamma -secretase catalytic activity or in other functions indirectly related to gamma -secretase catalysis (e,g. an activator of gamma -secretase, a substrate adaptor for gamma -secretase, or delivery of gamma -secretase to beta APP-containingcompartments).

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Documento generato il 04/04/20 alle ore 02:25:51