The structural and functional consequences of melatonin and serotonin on human αB-crystallin and their dual role in the eye lens transparency

Nourazaran, Mona; Yousefi, Reza; Moosavi-Movahedi, Faezeh; Panahi, Farhad; Hong, Jun; Moosavi-Movahedi, Ali A.

doi:10.1016/j.bbapap.2023.140928

Cited by 3 publications

(1 citation statement)

References 68 publications

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“…Further, while they are expressed, other crystallin encoding genes such as Crybg1 and Crybg3 are less likely to contribute to the refractive properties of the organoids based on previous findings [49,50]. Thus, our transcriptome expression analysis of 2D and 3D cultures, in addition to previous expression microarray data on the 21EM15 cell line [23] as well as the established knowledge on the function of several crystallins [51][52][53][54][55][56][57][58][59] offer an explanation toward the basis of refractive properties in these organoids. More importantly, these results also indicate that a subset of genes associated with lens development and fiber cell differentiation are induced under 3D culture conditions (Figure 2D).…”

Section: Discussionmentioning

confidence: 67%

Eye Lens Organoids Made Simple: Characterization of a New Three-Dimensional Organoid Model for Lens Development and Pathology

Duot,

Viel,

Viet

et al. 2023

Cells

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Cataract, the opacification of the lens, is the leading cause of blindness worldwide. Although effective, cataract surgery is costly and can lead to complications. Toward identifying alternate treatments, it is imperative to develop organoid models relevant for lens studies and drug screening. Here, we demonstrate that by culturing mouse lens epithelial cells under defined three-dimensional (3D) culture conditions, it is possible to generate organoids that display optical properties and recapitulate many aspects of lens organization and biology. These organoids can be rapidly produced in large amounts. High-throughput RNA sequencing (RNA-seq) on specific organoid regions isolated via laser capture microdissection (LCM) and immunofluorescence assays demonstrate that these lens organoids display a spatiotemporal expression of key lens genes, e.g., Jag1, Pax6, Prox1, Hsf4 and Cryab. Further, these lens organoids are amenable to the induction of opacities. Finally, the knockdown of a cataract-linked RNA-binding protein encoding gene, Celf1, induces opacities in these organoids, indicating their use in rapidly screening for genes that are functionally relevant to lens biology and cataract. In sum, this lens organoid model represents a compelling new tool to advance the understanding of lens biology and pathology and can find future use in the rapid screening of compounds aimed at preventing and/or treating cataracts.

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Section: Discussionmentioning

confidence: 67%

Eye Lens Organoids Made Simple: Characterization of a New Three-Dimensional Organoid Model for Lens Development and Pathology

Duot,

Viel,

Viet

et al. 2023

Cells

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Exploring the significance of potassium homeostasis in copper ion binding to human αB-Crystallin

Moosavi-Movahedi,

Saboury,

Ghasemi

et al. 2024

International Journal of Biological Macromolecules

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Melatonin, ATP, and Cataracts: The Two Faces of Crystallin Phase Separation

Loh,

Reiter

2024

Preprint

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The high concentration of crystallin proteins in the lens maintains transparency and clarity via a high refractive index that ensures optical quality. The chaperone-like activity of crystallins protects lenses against damaging protein aggregation and misfolding. The highly-crowded molecular environment in the lens fosters dehydration entropy-driven phase separation of crystallin proteins that can be activated by changes in temperature, ion and salt concentrations; and exposure to endogenous and exogenous stress including reactive oxygen species (ROS) and ultraviolet radiation. The sensitive balance between melatonin and adenosine triphosphate (ATP) prevents amorphous crystallin condensates from transitioning into amyloidogenic fibrillar aggregates present in late-stage cataracts. Melatonin exerts a multi-pronged strategy against cataractogenesis: first by scavenging ROS at condensate redox-reactive interfaces, effectively preventing the removal of water molecules from protein hydration shells that can cause the formation of pathogenic amyloid fibrils, then by complementing the ability of ATP to solubilize and disassemble protein aggregates via the adenosine moiety. Melatonin and ATP together strengthen hydrogen bonding, ensuring the proper ratio of bound water to free water, thereby preventing aberrant phase separation of crystallins and cataractogenesis. The progression of cataracts and glaucoma may be a reflection of an age-related decline in the production of melatonin and ATP exacerbated by exposure to light at night. Targeting this powerful, ancient synergy between melatonin and ATP offers an efficacious solution for ocular diseases driven by phase separation.

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The structural and functional consequences of melatonin and serotonin on human αB-crystallin and their dual role in the eye lens transparency

Cited by 3 publications

References 68 publications

Eye Lens Organoids Made Simple: Characterization of a New Three-Dimensional Organoid Model for Lens Development and Pathology

Eye Lens Organoids Made Simple: Characterization of a New Three-Dimensional Organoid Model for Lens Development and Pathology

Exploring the significance of potassium homeostasis in copper ion binding to human αB-Crystallin

Melatonin, ATP, and Cataracts: The Two Faces of Crystallin Phase Separation

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