Dataset Information

HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer’s disease pathology

ABSTRACT: 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.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Hidenori Homma

LAB HEAD: Hitoshi Okazawa

PROVIDER: PXD028089 | Pride | 2022-02-15

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	190417_U2OS-HMGB1-Ab_iTRAQ_180min_Phospho.group	Other
	Frac1-6-Human-set3.group	Other
	Frac1-6-Occi-set1-2nd.wiff	Wiff
	Frac1-6-Occi-set1-2nd.wiff.scan	Wiff
	Frac1-6-Occi-set1.wiff	Wiff

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HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer's disease pathology.

Tanaka Hikari H Kondo Kanoh K Fujita Kyota K Homma Hidenori H Tagawa Kazuhiko K Jin Xiaocen X Jin Meihua M Yoshioka Yuki Y Takayama Sumire S Masuda Hitomi H Tokuyama Rie R Nakazaki Yukoh Y Saito Takashi T Saido Takaomi T Murayama Shigeo S Ikura Teikichi T Ito Nobutoshi N Yamamori Yu Y Tomii Kentaro K Bianchi Marco E ME Okazawa Hitoshi H

Communications biology 20211011 1

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 ...[more]

PMID: 34635772

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