Targeted disruption of the mouse αA-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein αB-crystallin

Brady, John Paul; Garland, Donita; Duglas-Tabor, Yvonne; Wg, Robison; Groome, Anne B.; Wawrousek, E. F.

doi:10.1073/pnas.94.3.884

Cited by 314 publications

(262 citation statements)

References 31 publications

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“…1. We believe that some of these as yet undefined non-crystallin functions (38) of ␣A may be the reason for early cataracts in ␣A null mice (39). The observations made in this investigation may also explain why mutations in ␣A and ␣B have disparate phenotypic consequences (38).…”

Section: Discussionmentioning

confidence: 50%

αA-Crystallin and αB-Crystallin Reside in Separate Subcellular Compartments in the Developing Ocular Lens

Gangalum

Horwitz

Kohan

et al. 2012

Journal of Biological Chemistry

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Background:The small heat shock proteins, ␣A-crystallin and ␣B-crystallin are considered to be two subunits of one single monolithic lens protein, ␣-crystallin. Results: ␣A-Crystallin and ␣B-crystallin fractionate independent of each other and in two separate membrane compartments. Conclusion: ␣A-Crystallin and ␣B-crystallin are two independent proteins in the lens. Significance: These data provide functional insight into why ␣A-crystallin and ␣B-crystallin null mice have disparate phenotypes.

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Section: Discussionmentioning

confidence: 50%

αA-Crystallin and αB-Crystallin Reside in Separate Subcellular Compartments in the Developing Ocular Lens

Gangalum

Horwitz

Kohan

et al. 2012

Journal of Biological Chemistry

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“…Both proteins appear to have extensive nonlens roles (Nagineni and Bhat, 1992). Brady et al, (1997) showed that in αA crystallin knockout mice the lenses were smaller than wild type and developed opacification in the nucleus of the lens that became widespread with age. In the retina, studies on RPE from wild type and αA and αB knockout mice showed that both proteins were localized to the mitochondria and that a lack of alpha crystallins rendered RPE more susceptible to apoptosis following oxidative stress (Yaung et al, 2007).…”

Section: Mitochondrial Protective and Repair Systemsmentioning

confidence: 99%

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Brennan¹,

Kantorow²

2009

Experimental Eye Research

164

141

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Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself (Lin and Beal, 2006). In the anterior segment of the eye, oxidative stress has been linked to lens cataract (Truscott, 2005) and glaucoma (Tezel, 2006) while in the posterior segment of the eye oxidative stress has been associated with macular degeneration (Hollyfield et al., 2008). Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O 2 -) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (˙OH), hydrogen peroxide (H 2 O 2 ) and peroxynitrite (OONO -). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria (Hansford et al., 1997). Generation of superoxide at complex I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane (Kakkar and Singh 2007). While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Figure 1.0). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr)

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“…αA and αB crystallin knockout mice (αA crystallin (−/−) and αB crystallin (−/−)) were originally generated at the National Eye Institute by targeted gene disruption and were maintained in the 129 S6/SvEvTac background (Brady et al, 1997;. The wild type mouse strain was also129 S6/SvEvTac (Taconic Farms, Germantown, NY).…”

Section: Intravitreal Injection To Micementioning

confidence: 99%

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Yaung

Kannan

Wawrousek

et al. 2008

Experimental Eye Research

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This study evaluated the role of crystallins in retinal degeneration induced by chemical hypoxia. Wild type, αA-crystallin (−/−), and αB-crystallin (−/−) mice received intravitreal injection of 12 nmol (low dose), 33 nmol (intermediate dose) or 60 nmol (high dose) cobalt chloride (CoCl 2 ). Hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) stains were performed after 24 hours, 96 hours, and 1 week post-injection, while immunofluorescent stains for αA-and αB-crystallin were performed 1 week post-injection. The in vitro effects of CoCl 2 on αB-crystallin expression in ARPE-19 cells were determined by real time RT-PCR, Western blot, and confocal microscopy and studies evaluating subcellular distribution of αB-crystallin in the mitochondria and cytosol were also performed. Histologic studies revealed progressive retinal degeneration with CoCl 2 injection in wild type mice. Retinas of CoCl 2 injected mice showed transient increased expression of HIF-1α which was maximal 24 hours after injection. Intermediate dose CoCl 2 injection was associated with increased retinal immunofluorescence for both αA-and αB-crystallin; however, after high dose injection, increased retinal degeneration was associated with decreased levels of crystallin expression. Injection of CoCl 2 at either intermediate or high dose in αA-crystallin (−/−) and αB-crystallin (−/−) mice resulted in much more severe retinal degeneration compared to wild type eyes. A decrease in ARPE-19 total and cytosolic αB-crystallin expression with increasing CoCl2 treatment and an increase in mitochondrial αB-crystallin were found. We conclude that lack of α-crystallins accentuates retinal degeneration in chemically-induced hypoxia in vivo.

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Targeted disruption of the mouse αA-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein αB-crystallin

Cited by 314 publications

References 31 publications

αA-Crystallin and αB-Crystallin Reside in Separate Subcellular Compartments in the Developing Ocular Lens

αA-Crystallin and αB-Crystallin Reside in Separate Subcellular Compartments in the Developing Ocular Lens

Mitochondrial function and redox control in the aging eye: Role of MsrA and other repair systems in cataract and macular degenerations

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

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