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Published on: June 30, 2023
DNAJB6a deficiency induces tau pathology through IRE1α-Xbp1-induced mitochondria dysfunction
Xiu Chen1, Fang-Yuan Qian1, Na Zhao1
1Department of Neurology, Zhongda Hospital, School of Medicine, Jiangsu Provincial Key Laboratory of Brain Science and Medicine, Southeast University, Nanjing, Jiangsu 210009, China.
Zoological Research
|July 31, 2026
Summary
Researchers identified DNAJB6a as a key protein in Alzheimer's disease (AD) pathology. Its depletion activates endoplasmic reticulum stress and mitochondrial dysfunction, worsening AD symptoms, suggesting DNAJB6a as a potential therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) involves endoplasmic reticulum (ER) stress and mitophagy.
- Tau hyperphosphorylation is a key pathological feature in early AD.
- The precise molecular mechanisms underlying AD pathogenesis remain incompletely understood.
Purpose of the Study:
- To identify and characterize the role of DNAJB6a in Alzheimer's disease.
- To investigate the pathogenic mechanisms involving DNAJB6a in AD.
- To explore DNAJB6a as a potential therapeutic target for AD.
Main Methods:
- Bioinformatic screening of the DNAJB6 gene in AD patients.
- Analysis of DNAJB6a expression in APP/PS1 mouse models.
- Phenotypic analysis of DNAJB6a knockout mice.
- Investigation of ER stress pathways (HSPA5, IRE1α-XBP1) and mitochondrial function.
Main Results:
- DNAJB6 gene expression is decreased in AD patients' brains.
- DNAJB6a levels are reduced in APP/PS1 mice brains.
- DNAJB6a knockout mice display cognitive impairment, synaptic loss, and AD pathology.
- DNAJB6a depletion activates ER stress via HSPA5 downregulation.
- DNAJB6a deficiency exacerbates AD phenotypes through IRE1α-XBP1 mediated mitochondrial dysfunction.
Conclusions:
- DNAJB6a plays a crucial role in Alzheimer's disease pathogenesis.
- Reduced DNAJB6a levels contribute to ER stress and mitochondrial dysfunction in AD.
- DNAJB6a represents a potential therapeutic target for preventing or treating AD.
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