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

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.

Identification of 4 Novel Variants in 19 Families with Congenital Cataracts

“…Gene variants in CRYAA can potentially lead to endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) during lens development, causing cellular apoptosis and subsequently leading to cataract formation. [35] Variants in the CRYBA1 gene may lead to abnormalities in protein structure, preventing proper folding and assembly and thereby impacting the normal development and transparency of the lens. In addition to hereditary cataracts, CRYBA1 variants may also be associated with other ocular abnormalities such as corneal lesions and retinal diseases.…”

Expression of αA-crystallin (CRYAA) in vivo and in vitro models of age-related cataract and the effect of its silencing on HLEB3 cells

“…Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are induced when the body is exposed to adverse external stimuli like ROS, which has been established that can induce different cell death modes, including autophagy, apoptosis [ 35 ]. A study showed that prolonged activation of the unfolded protein reaction (UPR) pathway and severe stress response can cause proteotoxic and endoplasmic reticulum stress (ERS), which induced cell death in CRYAA-Y118D mutant mice [ 36 ]. Autophagy is a fundamental cellular requirement for achieving the mature structure, homeostasis, and transparency of the lens [ 14 ].…”

Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

“…The HSPB4 R54H and R54C substitutions have been also detected in mice strains showing recessive congenital cataract (Chang et al, 1996;Chang et al, 1999;Xia et al, 2006). Another mutation, the HSPB4 Y118D substitution, has been obtained in two mouse models (Xia et al, 2006;Jia et al, 2021). Both HSPB4 Y118D mouse models recapitulate the phenotype and the biochemical and functional observations reported, which are the increased protein insolubility and UPR pathway activation in response to ER stress (Xia et al, 2006;Li et al, 2017;Jia et al, 2021).…”

“…Another mutation, the HSPB4 Y118D substitution, has been obtained in two mouse models (Xia et al, 2006;Jia et al, 2021). Both HSPB4 Y118D mouse models recapitulate the phenotype and the biochemical and functional observations reported, which are the increased protein insolubility and UPR pathway activation in response to ER stress (Xia et al, 2006;Li et al, 2017;Jia et al, 2021). Mutations causing substantial modification of the CTD include the HSPB4 Q147Rfs*48 frameshift mutation or point mutations at the stop codon (Javadiyan et al, 2017;Marakhonov et al, 2020).…”