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Titolo:
C-terminal maturation fragments of presenilin 1 and 2 control secretion ofAPP alpha and A beta by human cells and are degraded by proteasome
Autore:
da Costa, CA; Ancolio, K; Checler, F;
Indirizzi:
CNRS, Inst Pharmacol Mol & Cellulaire, UPR 411, F-06560 Valbonne, France CNRS Valbonne France F-06560 llulaire, UPR 411, F-06560 Valbonne, France
Titolo Testata:
MOLECULAR MEDICINE
fascicolo: 3, volume: 5, anno: 1999,
pagine: 160 - 168
SICI:
1076-1551(199903)5:3<160:CMFOP1>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
FAMILIAL ALZHEIMERS-DISEASE; AMYLOID PRECURSOR PROTEIN; ENDOPLASMIC-RETICULUM; MISSENSE MUTATIONS; IN-VIVO; CLEAVAGE; LOCALIZATION; PEPTIDES; GENE; PHOSPHORYLATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Checler, F CNRS, Inst Pharmacol Mol & Cellulaire, UPR 411, 660 Route Lucioles, F-06560 CNRS 660 Route Lucioles Valbonne France F-06560 ioles, F-06560
Citazione:
C.A. da Costa et al., "C-terminal maturation fragments of presenilin 1 and 2 control secretion ofAPP alpha and A beta by human cells and are degraded by proteasome", MOL MED, 5(3), 1999, pp. 160-168

Abstract

Background: Most early-onset forms of Alzheimer's disease are due to missense mutations located on two homologous proteins named presenilin 1 and 2 (PS1 and PS2). Several lines of evidence indicate that PS 1 and PS2 undergo various post-transcriptional events including endoproteolytic cleavages, giving rise to 28-30 kD N-terminal (NTF) and 18-20 kD C-terminal (CTF) fragments that accumulate in vivo. Whether the biological activity of presenilinsis borne by the processed fragments or their holoprotein precursor remainsin question. We have examined the putative control of beta APP maturation by CTF-PS1/PS2 and the catabolic process of the latter proteins by the multicatalytic complex, proteasome. Materials and Methods: We transiently and stably transfected HEK293 cells with CTF:PS1 or CTF-PS2 cDNA. We examined these transfectants for their production of A beta 40, A beta 42, and APP alpha by immunoprecipitation usingspecific polyclonals. The effect of a series of proteases inhibitors on the immunoreactivity of CTF-PS1/PS2 was examined by Western blot. Finally, the influence of proteasome inhibitors on the generation of beta APP fragments by CTF-expressing cells was assessed by combined immunoprecipitation and densitometric analyses. Results: We showed that transient and stable transfection of CTF-PS1 and CTF-PS2 cDNAs in human cells leads to increased secretion of APP alpha and Abeta, the maturation products of beta APP. Furthermore, we demonstrated that two proteasome inhibitors, lactacystin and Z-IE(Ot-Bu)A-Leucinal, prevent the degradation of both CTFs. Accordingly, we established that proteasomeinhibitors drastically potentiate the phenotypic increased production of APP alpha and A beta elicited by CTP-PS1/PS2. Conclusion: Our data establish that the C-terminal products of PS1 and PS2maturation exhibit biological activity and in particular control beta APP maturation upstream to alpha-and beta/gamma-secretase cleavages. This function is directly controlled by the proteasome that modulates the intracellular concentration of CTFs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/03/20 alle ore 00:51:54