Proteomic characterization of the human lens and Cataractogenesis

Abstract

Introduction: The goal of this review is to highlight the triumphs and frontiers in measurement of the lens proteome as it relates to onset of age-related nuclear cataract. As global life expectancy increases, so too does the frequency of age-related nuclear cataracts. Molecular therapeutics do not exist for delay or relief of cataract onset in humans. Since lens fiber cells are incapable of protein synthesis after initial maturation, age-related changes in proteome composition and post-translational modification accumulation can be measured with various techniques. Several of these modifications have been associated with cataract onset.

Areas covered: We discuss the impact of long-lived proteins on the lens proteome and lens homeostasis as well as proteomic techniques that may be used to measure proteomes at various levels of proteomic specificity and spatial resolution.

Expert opinion: There is clear evidence that several proteome modifications are correlated with cataract formation. Past studies should be enhanced with cutting-edge, spatially resolved mass spectrometry techniques to enhance the specificity and sensitivity of modification detection as it relates to cataract formation.

Keywords: Lens; aging; cataract; long-lived proteins; mass spectrometry; spatial proteomics.

Figure 1 –

Black-and-white Scheimpflug image of two human lenses along axial plane: A) a healthy lens with limited light refraction, B) a lens with ARNC. Light is strongly scattered through the lens nucleus. Figure adapted from Yonova-Doing et al., 2016.

Figure 2 -

Cartoon of the axially sliced ocular lens. An enlarged depiction of the inner nucleus (yellow) is surrounded by growth rings of the outer nucleus (orange) and outer cortex (green). Peripheral fibers retain organelles, are differentiated from epithelial cells (grey), and elongate to sutures at each pole, here depicted as a black line. Light passes through the cornea anterior to the lens and is transmitted to the retina positioned posterior to the lens. The entire lens is retained in a collagenous capsule (blue). Lens fibers are not drawn to scale.

Figure 3 –

The spatially resolved abundance of intact and C-terminal truncated (Asn259 and Asn246) AQP0 in aging human lenses is visualized with MALDI imaging mass spectrometry. Intact AQP0 is not detected in the nucleus by the age of 21. Figure adapted from Wenke et al., 2015.

Figure 4 -

2DGE of a 42-year old lens with manual dissection and separate analysis of A) the outer cortex, B) outer nucleus, C) inner nucleus, D) the innermost region of the inner nucleus, formed in embryogenesis. Several α-crystallin, β-crystallin and γ-crystallin species are annotated in A. Second dimension of focusing is from acidic (left) to basic (right). Figure from Garland et al., 1995.

Figure 5 -

Summary of relative spatial resolution, proteome networks coverage and rate of detection for each of the discussed technologies. Differences are not uniform, especially in comparisons of spatial resolution.