Dual Roles of Proteasome in the Metabolism of Presenilin 1

• Published in: Journal of neurochemistry Vol. 72; no. 1; pp. 255 - 261
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Oxford UK Blackwell Science Ltd 01.01.1999; Blackwell
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - pharmacology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amino Acid Sequence; Biological and medical sciences; Brain Chemistry - physiology; Coumarins - pharmacology; Cysteine Endopeptidases - drug effects; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Glycoproteins - pharmacology; Humans; Kidney - cytology; Medical sciences; Membrane Proteins - metabolism; Molecular Sequence Data; Multienzyme Complexes - drug effects; Multienzyme Complexes - metabolism; Mutation - physiology; Neuroblastoma; Neurology; Peptide Fragments - genetics; Peptide Fragments - metabolism; Precipitin Tests; Presenilin; Presenilin-1; Proteasome; Proteasome Endopeptidase Complex; Proteolytic processing; Serine Proteinase Inhibitors - pharmacology; Sulfones - pharmacology; Trypsin Inhibitors - pharmacology; Tumor Cells, Cultured; Human; Multicatalytic endopeptidase complex; Nervous system diseases; Enzyme; Alzheimer disease; Presenilin; Metabolism; In vitro; Cerebral disorder; Peptidases; Cell line; Proteolysis; Central nervous system disease; Hydrolases; Degenerative disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1999.0720255.x

: 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.