Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model
| Autor: | Xiangjun Chen, Ailing Wang, Zhekun Jia, Chenxi Fu, Ke Yao |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Programmed cell death Mutant Protein aggregation Biology alpha-Crystallin A Chain Article Transcriptome Mice 03 medical and health sciences 0302 clinical medicine Crystallin Animals Alleles Ecology Evolution Behavior and Systematics Ecology Endoplasmic reticulum unfolded protein response αa-crystallin eye diseases Cell biology Disease Models Animal 030104 developmental biology QL1-991 cataract Apoptosis Mutation endoplasmic reticulum stress 030221 ophthalmology & optometry Unfolded protein response Animal Science and Zoology sense organs Zoology |
| Zdroj: | Zoological Research, Vol 42, Iss 3, Pp 300-309 (2021) Zoological Research |
| ISSN: | 2095-8137 |
| DOI: | 10.24272/j.issn.2095-8137.2020.354 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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