title: Phosphorylation of serine 349 of p62 in Alzheimer's disease brain.
abstract: BACKGROUND
  Extensive research on p62 has established its role in oxidative stress, protein degradation and in several diseases such as Paget's disease of the bone, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Importantly, previous studies showed that p62 binds directly to Keap1, which is a ubiquitin E3 ligase responsible for degrading Nrf2. Indeed, colocalisation of p62 and Keap1 occurs in tumorigenesis and neurodegeneration. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap1. However, it remains largely unknown whether p62 is phosphorylated in the Keap1-interacting region under neurodegenerative conditions.
  
  
  RESULTS
  To answer this question, we generated an antibody against phosphorylated S349 (P-S349) of p62 and showed that S349 is phosphorylated following disruption of protein degradation. In particular, the ratio of P-S349 to total p62 levels was significantly increased in the brains with Alzheimer's disease (AD) compared with controls. We also compared the reactivity of the P-S349 antibody with P-S403 of p62 and showed that these two phosphorylated sites on p62 cause different responses with proteasome inhibition and show distinct localisation patterns in AD brains. In addition to disruption of protein degradation systems, activation of oxidative stress can induce P-S349.
  
  
  CONCLUSIONS
  These results support the hypothesis that disruption of protein degradation systems and sustained activation of the Keap1-Nrf2 system occur in the brains with AD.
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. kunikazu@cc.hirosaki-u.ac.jp.
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tanji
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miki
authors.forename: Taku
authors.initials: T
authors.lastname: Ozaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maruyama
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Junsei
authors.initials: J
authors.lastname: Mimura
authors.forename: Tomoh
authors.initials: T
authors.lastname: Matsumiya
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000071456:Sequestosome-1 Protein; D012694:Serine / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D015853:Cysteine Proteinase Inhibitors; D010446:Peptide Fragments; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D012694:Serine