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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.
Abstract:
Endoplasmic reticulum (ER) stress and mitophagy have been indicated in the early stage of Alzheimer's disease (AD), in which tau hyperphosphorylation is one major pathological alteration. However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, the DnaJ (Hsp40) homolog, subfamily B, member 6a (DNAJB6a), and elucidates its potential pathogenic role in AD. The DNAJB6 gene is systematically screened using bioinformatics methods, confirming its decreased expression in AD patients' brains. And decreased DNAJB6a was found in the brains of the APP/PS1 mice compared to the control mice. DNAJB6a -/- mice exhibited cognitive impairment, synaptic loss and the pathological phenotypes of AD. Depletion of DNAJB6a led to activated ER stress depending on the downregulation of heat shock 70kDa protein 5 (HSPA5). Furthermore, DNAJB6a deficiency induced and accelerated AD-like phenotypes through activating IRE1α-XBP1 induced mitochondria dysfunction. These findings highlight DNAJB6a as a potential key target for preventing AD pathology.
Insights
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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