Dual roles of proteasome in the metabolism of presenilin 1.
Presenilin 1 (PS1) has been identified as a causative gene for most early-onset familial Alzheimer's disease. Biochemical studies revealed that PS1 exists predominantly as two processed fragments in cells and brain tissues. We prepared stably transfected cells expressing the wild-type and familial Alzheimer's disease-associated mutants of PS1 and investigated the enzyme that participates in the metabolism of PS1. After treatment of the cells with proteasome inhibitors, the full-length PS1 was significantly accumulated. 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 be processed, on treatment of the transfected cells with lactacystin indicated that proteasome can degrade full-length PS1. A synthetic peptide that includes the processing region of PS1 was cleaved by 20S proteasome at the putative processing sites after Met288 and Glu299. 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.
Honda
T
T
Laboratory for Alzheimer's Disease, Brain Science Institute, RIKEN, Saitama, Japan.
Yasutake
K
K
Nihonmatsu
N
N
Mercken
M
M
Takahashi
H
H
Murayama
O
O
Murayama
M
M
Sato
K
K
Omori
A
A
Tsubuki
S
S
Saido
T C
TC
Takashima
A
A
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001923:Brain Chemistry / Q000502:physiology*; D003374:Coumarins / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D049934:Isocoumarins; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests; D053764:Presenilin-1; D046988:Proteasome Endopeptidase Complex; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D049934:Isocoumarins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; D014361:Trypsin Inhibitors; C039304:calpain inhibitors; C067713:lactacystin; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; C046235:3,4-dichloroisocoumarin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine