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Dual Roles of Proteasome in the Metabolism of Presenilin 1
Author(s) -
Honda Toshiyuki,
Yasutake Kaori,
Nihonmatsu Naomi,
Mercken Mark,
Takahashi Hiroshi,
Murayama Ohoshi,
Murayama Miyuki,
Sato Kazuki,
Omori Akira,
Tsubuki Satoshi,
Saido Takaomi C.,
Takashima Akihiko
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720255.x
Subject(s) - lactacystin , presenilin , proteasome , transfection , biology , proteolysis , mutant , biochemistry , microbiology and biotechnology , exon , proteasome inhibitor , alzheimer's disease , gene , enzyme , disease , medicine
: Presenilin 1 (PS1) has been identified as a causativegene for most early‐onset familial Alzheimer's disease. Biochemical studiesrevealed that PS1 exists predominantly as two processed fragments in cells andbrain tissues. We prepared stably transfected cells expressing the wild‐typeand familial Alzheimer's disease‐associated mutants of PS1 and investigatedthe enzyme that participates in the metabolism of PS1. After treatment of thecells with proteasome inhibitors, the full‐length PS1 was significantlyaccumulated. The levels of N‐ and C‐terminal fragments were also increased.The accumulation of PS1 with a deletion of exon 10, which is unable to beprocessed, on treatment of the transfected cells with lactacystin indicatedthat proteasome can degrade full‐length PS1. A synthetic peptide that includesthe processing region of PS1 was cleaved by 20S proteasome at the putativeprocessing sites after Met 288 and Glu 299 . Metabolic labeling experiments showed that the appearance of the N‐terminal fragment was attenuated by the inhibitor. Finally, 28‐kDa N‐ and 20‐kDa C‐terminal fragments were generated by purified PS1 in vitro. These data indicated that the proteasome pathway is involved in PS1 processing. These results demonstrate that the proteasome pathway plays dual roles in processing and degradation of PS1.