Distribution of Ferritin and Redox-active Transition Metals in Normal and Cataractous Human Lenses

Garner, Brett; Roberg, Karin; Qian, Mingwei; Eaton, John W.; Truscott, Roger J.W.

doi:10.1006/exer.2000.0912

Cited by 37 publications

(30 citation statements)

References 41 publications

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“…These chelatable Zn 2+ ions, which in neurons are localized primarily in synaptic vesicles of so-called zinc-enriched neurons, can be detected by either fluorescence or AMG techniques. Although AMG detects copper (85) and iron (86), as well as zinc (62,87,88), ZP1 is highly selective for Zn 2+ and its intrinsic fluorescence is quenched by copper, iron, manganese, and cobalt ions (38,66,89). Thus, the fact that we observed similar changes in Zn 2+ with AMG and ZP1 reinforces the conclusion that elevation of Zn 2+ itself is occurring after NC.…”

Section: Discussionsupporting

confidence: 83%

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Andereggen

Yuki

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

129

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Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn 2+ ) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn 2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn 2+ accumulation in amacrine cell processes involves the Zn 2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn 2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn 2+ chelation extends for several days after nerve injury. These results show that retinal Zn 2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn 2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.T he optic nerve has been widely used to investigate the response of CNS neurons to injury because of its accessibility, anatomy, and functional importance. Under normal circumstances, retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate axons after the optic nerve has been damaged and soon undergo cell death, leaving victims of traumatic or ischemic nerve injury or degenerative conditions, such as glaucoma, with permanent visual losses. Optic nerve injury leads to numerous pathological changes in RGCs and reversing some of these changes improves cell survival, although these effects are often transitory and for the most part promote little or no axon regeneration (1-10). Regeneration per se can be induced by intraocular inflammation combined with elevated cAMP (11, 12), counteracting cell-intrinsic (13-15) or cellextrinsic (16, 17) suppressors of axon growth, oncomodulin and other growth factors (18-22), or elevated physiological activity (23,24). Some of these treatments act synergistically and enable a modest number of RGCs to reestablish connections with appropriate target areas in the brain (25-27). However, although these studies show that successful regeneration can occur in principle, most RGCs eventually die after optic nerve injury, and to date only a small fraction of surviving RGCs have been induced to regenerate axons (27). These observations imply the existence of other major, as yet unknown suppressors of cell survival and regeneration. Our results point to zinc dysregulation as a critical factor.Zinc is essential for many cellular functions. Covalently bound zinc is required for the activity of numerous enzymes and t...

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Section: Discussionsupporting

confidence: 83%

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Andereggen

Yuki

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

129

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“…In addition, nuclei from more advanced lenses (Type IV) produce more hydroxyl radicals when incubated with exogenous H 2 O 2 than do Type II nuclei (Garner, Davies and Truscott, 2000a). This re¯ects both increased content of Fe as well as an increased redox availability (Garner et al, 2000b).…”

Section: Introductionmentioning

confidence: 98%

The Presence of a Human UV Filter within the Lens Represents an Oxidative Stress

Berry

Truscott

2001

Experimental Eye Research

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“…Iron is implicated in cataract development, due to its ability to catalyze the formation of free radicals. Aging cataractous lenses have higher levels of iron [3] and an increased capacity for free-radical formation [4]. Excess iron is normally safely stored in ferritin, a ubiquitous protein with a highly conserved structure.…”

Section: Introductionmentioning

confidence: 99%

“…Ferritin is present throughout the entire noncataractous and cataractous lens [3,7]. However, ferritin chains are significantly altered in lens fiber cells, in comparison to those of lens epithelial cells and other tissues [7].…”

Section: Introductionmentioning

confidence: 99%

Changes in Ferritin H- and L-Chains in Canine Lenses with Age-Related Nuclear Cataract

Goralska

Nagar

Colitz

et al. 2009

Invest. Ophthalmol. Vis. Sci.

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PURPOSE To determine potential differences in the characteristics of the iron storage protein, ferritin and its heavy (H) and light (L) subunits in fiber cells from cataractous and normal lenses of older dogs. METHODS Lens fiber cell homogenates were analyzed by SDS-PAGE and ferritin chains were immunodetected with ferritin chain-specific antibodies. Ferritin concentration was measured by ELISA. Immunohistochemistry was used to localize ferritin chains in lens sections. RESULTS The concentration of assembled ferritin was comparable in normal and cataractous lenses of similarly aged dogs. The ferritin L-chain detected in both lens types was modified and was about 11 kDa larger (30 kDa) than standard L-chain (19 kDa) purified from canine liver. The H-chain identified in cataractous fiber cells (29 kDa) differed from 21 kDa standard canine H-chain and from 12 kDa modified H-chain present in fiber cells of normal lenses. Histologic analysis revealed that the H-chain was distributed differently throughout cataractous lenses when compared to normal lenses. There was also a difference in subunit makeup of assembled ferritin between the two lens types. Ferritin from cataractous lenses contained more H-chain and bound 11-fold more iron than ferritin from normal lenses. CONCLUSIONS There are significant differences in the characteristics of ferritin H-chain and its distribution in canine cataractous lenses as compared to normal lenses. The higher content of H-chain in assembled ferritin allows this molecule to sequester more iron. In addition the accumulation of H-chain in deeper fiber layers of the lens may be part of a defense mechanism by which the cataractous lens limits iron-catalyzed oxidative damage.

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Distribution of Ferritin and Redox-active Transition Metals in Normal and Cataractous Human Lenses

Cited by 37 publications

References 41 publications

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

The Presence of a Human UV Filter within the Lens Represents an Oxidative Stress

Changes in Ferritin H- and L-Chains in Canine Lenses with Age-Related Nuclear Cataract

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