New insights into change of lens proteins’ stability with ageing under physiological conditions

Luo, Chenqi; Xu, Junjie; Fu, Chenxi; Yao, Ke; Chen, Xiangjun

doi:10.1136/bjophthalmol-2021-319834

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…A prominent example of the deleterious effects of protein aggregation occurs in the ocular lens. Accumulation of age-dependent damage to lens proteins induced by multiple factors, such as UV radiation and oxidation, leads to changes in their stability and solubility ( Kopylova et al, 2011 ; Vetter et al, 2020 ; Luo et al, 2021 ). Gradual nucleation of aggregation-prone proteins eventually leads to large condensates that result in lens opacification, light scattering, and potentially age-related cataract ( Moreau and King, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Interplay between Nrf2 and αB-crystallin in the lens and heart of zebrafish under proteostatic stress

Park

MacGavin

Niederbrach

et al. 2023

Front. Mol. Biosci.

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A coordinated oxidative stress response, partly triggered by the transcription factor Nrf2, protects cells from the continual production of reactive oxygen species. Left unbuffered, reactive oxygen species can lead to protein aggregation that has been implicated in a spectrum of diseases such as cataract of the ocular lens and myopathy of the heart. While proteostasis is maintained by diverse families of heat shock proteins, the interplay between the oxidative and proteostatic stress responses in the lens and heart has not been investigated. Capitalizing on multiple zebrafish lines that have compromised function of Nrf2 and/or the two zebrafish small heat shock proteins αBa- and αBb-crystallin, we uncovered a transcriptional relationship that leads to a substantial increase in αBb-crystallin transcripts in the heart in response to compromised function of Nrf2. In the lens, the concomitant loss of function of Nrf2 and αBa-crystallin leads to upregulation of the cholesterol biosynthesis pathway, thus mitigating the phenotypic consequences of the αBa-crystallin knockout. By contrast, abrogation of Nrf2 function accentuates the penetrance of a heart edema phenotype characteristic of embryos of αB-crystallin knockout lines. Multiple molecular pathways, such as genes involved in extracellular interactions and implicated in cardiomyopathy, are revealed from transcriptome profiling, thus identifying novel targets for further investigation. Together, our transcriptome/phenotypic analysis establishes an intersection between oxidative stress and chaperone responses in the lens and heart.

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Section: Introductionmentioning

confidence: 99%

Interplay between Nrf2 and αB-crystallin in the lens and heart of zebrafish under proteostatic stress

Park

MacGavin

Niederbrach

et al. 2023

Front. Mol. Biosci.

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“…Cataract, which is characterized by opacity of the eye lens, is a prevalent disease associated with protein aggregation and the leading cause of blindness and visual impairment worldwide ( Asbell et al, 2020 ). Misfolding and aggregation of different lens crystallins, which account for about 90% of the water soluble proteins of the lens, are considered the major pathogenic factors responsible for all types of cataracts ( Luo et al, 2021 ). Furthermore, mutations in various genes have been linked to both age-related and congenital cataracts, and among the more than 100 genes reported in congenital cataracts, crystallin mutations account for almost half of the total number of mutations, although most of their pathogenetic mechanisms causing cataracts remain unclear ( Li et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability

Ren

Zhang

et al. 2022

Front. Mol. Biosci.

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Cataract, opacity of the eye lens, is the leading cause of visual impairment worldwide. The crucial pathogenic factors that cause cataract are misfolding and aggregation of crystallin protein. βB1‐crystallin, which is the most abundant water‐soluble protein in mammalian lens, is essential for lens transparency. A previous study identified the missense mutation βB1‐S93R being responsible for congenital cataract. However, the exact pathogenic mechanism causing cataract remains unclear. The S93 residue, which is located at the first Greek‐key motif of βB1‐crystallin, is highly conserved, and its substitution to Arginine severely impaired hydrogen bonds and structural conformation, which were evaluated via Molecular Dynamic Simulation. The βB1‐S93R was also found to be prone to aggregation in both human cell lines and Escherichia coli. Then, we isolated the βB1‐S93R variant from inclusion bodies by protein renaturation. The βB1-S93R mutation exposed more hydrophobic residues, and the looser structural mutation was prone to aggregation. Furthermore, the S93R mutation reduced the structural stability of βB1-crystallin when incubated at physiological temperature and made it more sensitive to environmental stress, such as UV irradiation or oxidative stress. We also constructed a βB1-S93R cellular model and discovered that βB1-S93R was more sensitive to environmental stress, causing not only aggregate formation but also cellular apoptosis and impaired cellular viability. All of the results indicated that lower solubility and structural stability, sensitivity to environmental stress, vulnerability to aggregation, and impaired cellular viability of βB1-S93R might be involved in cataract development.

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Model acetylcholinesterase‐Fc fusion glycoprotein biotechnology system for the manufacture of an organophosphorus toxicant bioscavenging countermeasure

Biel,

Faison,

Matthews

et al. 2024

Bioengineering & Transla Med

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Organophosphate (OP) toxicants remain an active threat to public health and to warfighters in the military. Current countermeasures require near immediate administration following OP exposure and are reported to have controversial efficacies. Acetylcholinesterase (AChE) fused to the human immunoglobulin 1 (IgG1) Fc domain (AChE‐Fc) is a potential bioscavenger for OP toxicants, but a reproducible AChE‐Fc biomanufacturing strategy remains elusive. This report is the first to establish a comprehensive laboratory‐scale bioprocessing strategy that can reproducibly produce AChE‐Fc and AChE(W86A)‐Fc which is a mutated AChE protein with reduced enzymatic activity. Characterization studies revealed that AChE‐Fc and AChE(W86A)‐Fc are N‐glycosylated dimeric fusion glycoproteins but only AChE‐Fc had the capability to bind to paraoxon (a model OP). This AChE‐Fc fusion glycoprotein bioprocessing strategy can be leveraged during industrial biomanufacturing development, while the research‐grade AChE‐Fc proteins can be used to determine the potential clinical relevance of the countermeasure against OP toxicants.

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New insights into change of lens proteins’ stability with ageing under physiological conditions

Cited by 5 publications

References 21 publications

Interplay between Nrf2 and αB-crystallin in the lens and heart of zebrafish under proteostatic stress

Interplay between Nrf2 and αB-crystallin in the lens and heart of zebrafish under proteostatic stress

Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability

Model acetylcholinesterase‐Fc fusion glycoprotein biotechnology system for the manufacture of an organophosphorus toxicant bioscavenging countermeasure

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