Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

Zhe-Kun Jia; Chen-Xi Fu; Ai-Ling Wang; Ke Yao; Xiang-Jun Chen

doi:10.24272/j.issn.2095-8137.2020.354

Volume 42 Issue 3

May 2021

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Article Navigation > Zoological Research > 2021 > 42(3): 300-309

Zhe-Kun Jia, Chen-Xi Fu, Ai-Ling Wang, Ke Yao, Xiang-Jun Chen. Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model. Zoological Research, 2021, 42(3): 300-309. doi: 10.24272/j.issn.2095-8137.2020.354

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Zhe-Kun Jia, Chen-Xi Fu, Ai-Ling Wang, Ke Yao, Xiang-Jun Chen. Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model. Zoological Research, 2021, 42(3): 300-309. doi: 10.24272/j.issn.2095-8137.2020.354

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Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

doi: 10.24272/j.issn.2095-8137.2020.354

Zhe-Kun Jia¹,
Chen-Xi Fu¹,
Ai-Ling Wang²,
Ke Yao^{1
,
,},
Xiang-Jun Chen^{1, 2
,
,}

1.
Eye Center of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
2.
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310020, China

Funds: This study was supported by the National Natural Science Foundation of China (31872724, 81900837, 81870641, 82070939) and Zhejiang Province Key Research and Development Program (2019C03091, 2020C03035)

More Information

Corresponding author: E-mail: chenxiangjun@zju.edu.cn; xlren@zju.edu.cn
Received Date: 2020-12-07
Accepted Date: 2021-03-19

Published Online: 2021-04-07

Publish Date: 2021-05-18

Abstract

Abstract

As small heat shock proteins, α-crystallins function as molecular chaperones and inhibit the misfolding and aggregation of β/γ-crystallins. Genetic mutations of CRYAA are associated with protein aggregation and cataract occurrence. One possible process underlying cataract formation is that endoplasmic reticulum stress (ERS) induces the unfolded protein response (UPR), leading to apoptosis. However, the pathogenic mechanism related to this remains unexplored. Here, we successfully constructed a cataract-causing CRYAA (Y118D) mutant mouse model, in which the lenses of the CRYAA-Y118D mutant mice showed severe posterior rupture, abnormal morphological changes, and aberrant arrangement of crystallin fibers. Histological analysis was consistent with the clinical pathological characteristics. We also explored the pathogenic factors involved in cataract development through transcriptome analysis. In addition, based on key pathway analysis, up-regulated genes in CRYAA-Y118D mutant mice were implicated in the ERS-UPR pathway. This study showed that prolonged activation of the UPR pathway and severe stress response can cause proteotoxic and ERS-induced cell death in CRYAA-Y118D mutant mice.
- Cataract,
- αA-crystallin,
- Unfolded protein response,
- Endoplasmic reticulum stress

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References(54)

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