PXD028089

PXD028089 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2021-08-24 03:08:44	ID requested
⏵ 1	2022-02-15 09:11:27	announced

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]

submitter keyword: Alzheimer's disease, Ku70, phosphorylation, HMGB1

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

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PRIDE project URI

• PRIDE
  1. PXD028089
     1. Label: PRIDE project
     2. Name: HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer’s disease pathology