α- and β-Crystallins Modulate the Head Group Order of Human Lens Membranes during Aging

Zhu, Xiangjia; Gaus, Katharina; Lü, Yi; Magenau, Astrid; Truscott, Roger J.W.; Mitchell, Todd W.

doi:10.1167/iovs.09-4947

Cited by 20 publications

(24 citation statements)

References 49 publications

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“…Recent data suggest that the reason for the onset of the barrier is due to the binding of crystallins to fiber cell membranes (Friedrich and Truscott 2009) and in this way the membrane pores are occluded. In vitro studies suggest that α-crystallin binding to human lens lipids increases with age ) and this may be responsible for altering the physical properties of the fiber cell membranes (Zhu et al 2010a). On the basis of the data in this manuscript, it could be proposed that the binding of proteins after middle age may be traced to a marked change in the lipid composition of the cell membranes.…”

Section: Discussionmentioning

confidence: 79%

Instability of the cellular lipidome with age

Hughes

Deeley

Blanksby

et al. 2011

AGE

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The human lens nucleus is formed in utero, and from birth onwards, there appears to be no significant turnover of intracellular proteins or membrane components. Since, in adults, this region also lacks active enzymes, it offers the opportunity to examine the intrinsic stability of macromolecules under physiological conditions. Fifty seven human lenses, ranging in age from 12 to 82 years, were dissected into nucleus and cortex, and the nuclear lipids analyzed by electrospray ionization tandem mass spectrometry. In the first four decades of life, glycerophospholipids (with the exception of lysophosphatidylethanolamines) declined rapidly, such that by age 40, their content became negligible. In contrast the level of ceramides and dihydroceramides, which were undetectable prior to age 30, increased approximately 100-fold. The concentration of sphingomyelins and dihydrosphingomyelins remained unchanged over the whole life span. As a consequence of this marked alteration in composition, the properties of fiber cell membranes in the centre of young lenses are likely to be very different from those in older lenses. Interestingly, the identification of age 40 years as a time of transition in the lipid composition of the nucleus coincides with previously reported macroscopic changes in lens properties (e.g., a massive age-related increase in lens stiffness) and related pathologies such as presbyopia. The underlying reasons for the dramatic change in the lipid profile of the human lens with age are not known, but are most likely linked to the stability of some membrane lipids in a physiological environment.

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Section: Discussionmentioning

confidence: 79%

Instability of the cellular lipidome with age

Hughes

Deeley

Blanksby

et al. 2011

AGE

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“…For example, peptides derived from breakdown of α-crystallin may promote protein aggregation – a key process in lens aging and cataract. Peptides from age-related cleavage of γS-crystallin lodge tightly into fibre cell membranes and potentially alter water dynamics [43] in a way that is consistent with that associated with older lens membranes [44]. Impaired water flow will presumably also affect solute transport (e.g.…”

Section: Spontaneous Cleavage Of Peptide Bondsmentioning

confidence: 99%

The etiology of human age-related cataract. Proteins don't last forever

Truscott

Friedrich

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

103

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Background It is probable that the great majority of human cataract results from the spontaneous decomposition of long-lived macromolecules in the human lens. Breakdown/reaction of long-lived proteins is of primary importance and recent proteomic analysis has enabled the identification of the particular crystallins, and their exact sites of amino acid modification. Scope of review Analysis of proteins from cataractous lenses revealed that there are sites on some structural proteins that show a consistently greater degree of deterioration than age-matched normal lenses. Major conclusions The most abundant posttranslational modification of aged lens proteins is racemization. Deamidation, truncation and crosslinking, each arising from the spontaneous breakdown of susceptible amino acids within proteins, are also present. Fundamental to an understanding of nuclear cataract etiology, it is proposed that once a certain degree of modification at key sites occurs, that protein-protein interactions are disrupted and lens opacification ensues. General Significance Since long-lived proteins are now recognized to be present in many other sites of the body, such as the brain, the information gleaned from detailed analyses of degraded proteins from aged lenses will apply more widely to other age-related human diseases.

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“…As with other protein chaperones, α-crystallins also assist in the assembly/disassembly of protein complexes and also influence phospholipid head group organization (Zhu et al, 2010a), They are also nucleotide-independent protein chaperones, a distinct advantage in the low oxygen tension environment of the lens (Barbazetto et al, 2004; Beebe et al, 2014) where ATP is replenished by glycolysis (Cheng et al, 1991). The lens α-crystallins comprise two proteins, αA- and αB-crystallin.…”

Section: Sustaining the Solubility Of Lens Proteinsmentioning

confidence: 99%

“…The α-crystallins become attached to the lipid membrane (Borchman and Tang, 1996; Grami et al, 2005; Maddala and Rao, 2005) and their association with lens membranes coincides with decreased lens compliance (Heys et al, 2007). The α-crystallins influence the head group organization of the phospholipids (Zhu et al, 2010a). Other lens proteins also become associated as the membranes age (Truscott et al, 2011) and it is thought that this will also contribute to the complexity of the protein complement on the membranes in aged lenses.…”

Section: Dietary Factors Associated With Altered Lens Cataract Risksmentioning

confidence: 99%

Small molecules, both dietary and endogenous, influence the onset of lens cataracts

Barnes

Quinlan

2017

Experimental Eye Research

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How the lens ages successfully is a lesson in biological adaption and the emergent properties of its complement of cells and proteins. This living tissue contains some of the oldest proteins in our bodies and yet they remain functional for decades, despite exposure to UV light, to reactive oxygen species and all the other hazards to protein function. This remarkable feat is achieved by a shrewd investment in very stable proteins as lens crystallins, by providing a reservoir of ATP-independent protein chaperones unequalled by any other tissue and by an oxidation-resistant environment. In addition, glutathione, a free radical scavenger, is present in mM concentrations and the plasma membranes contain oxidation-resistant sphingolipids, so what compromises lens function as it ages? In this review, we examine the role of small molecules in the prevention or causation of cataracts, including those associated with diet, metabolic pathways and drug therapy (steroids).

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α- and β-Crystallins Modulate the Head Group Order of Human Lens Membranes during Aging

Cited by 20 publications

References 49 publications

Instability of the cellular lipidome with age

Instability of the cellular lipidome with age

The etiology of human age-related cataract. Proteins don't last forever

Small molecules, both dietary and endogenous, influence the onset of lens cataracts

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