PXD028089 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer’s disease pathology |
Description | DNA damage is increased in Alzheimer’s disease (AD), while the underlying mechanisms are unknown. Here, we employ comprehensive phosphoproteome analysis, and identify abnormal phosphorylation of 70 kDa subunit of Ku antigen (Ku70) at Ser77/78, which prevents Ku70-DNA interaction, in human AD postmortem brains. The abnormal phosphorylation inhibits accumulation of Ku70 to the foci of DNA double strand break (DSB), impairs DNA damage repair and eventually causes transcriptional repression-induced atypical cell death (TRIAD). Cells under TRIAD necrosis reveal senescence phenotypes. Extracellular high mobility group box 1 (HMGB1) protein, which is released from necrotic or hyper-activated neurons in AD, binds to toll-like receptor 4 (TLR4) of neighboring neurons, and activates protein kinase C alpha (PKCα) that executes Ku70 phosphorylation at Ser77/78. Administration of human anti-HMGB1 antibody to post-symptomatic AD model mice decreases neuronal DSBs, suppresses secondary TRIAD necrosis of neurons, prevents escalation of neurodegeneration, and ameliorates cognitive symptoms. TRIAD shares multiple features with senescence. These results newly unravel the HMGB1-Ku70 axis that accounts for the increase of neuronal DNA damage and secondary enhancement of TRIAD, the cell death phenotype of senescence, in AD. |
HostingRepository | PRIDE |
AnnounceDate | 2022-02-15 |
AnnouncementXML | Submission_2022-02-15_09:11:26.266.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Hidenori Homma |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue |
Instrument | TripleTOF 5600 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2021-08-24 03:08:44 | ID requested | |
⏵ 1 | 2022-02-15 09:11:27 | announced | |
Publication List
Tanaka H, Kondo K, Fujita K, Homma H, Tagawa K, Jin X, Jin M, Yoshioka Y, Takayama S, Masuda H, Tokuyama R, Nakazaki Y, Saito T, Saido T, Murayama S, Ikura T, Ito N, Yamamori Y, Tomii K, Bianchi ME, Okazawa H, HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer's disease pathology. Commun Biol, 4(1):1175(2021) [pubmed] |
Keyword List
submitter keyword: Alzheimer's disease, Ku70, phosphorylation, HMGB1 |
Contact List
Hitoshi Okazawa |
contact affiliation | 1Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University |
contact email | okazawa-tky@umin.ac.jp |
lab head | |
Hidenori Homma |
contact affiliation | Tokyo Medical and Dental University |
contact email | homma.npat@mri.tmd.ac.jp |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD028089 |
PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD028089
- Label: PRIDE project
- Name: HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer’s disease pathology