Multiple, parallel cellular suicide mechanisms participate in photoreceptor cell death

Lohr, Heather R.; Kuntchithapautham, Kannan; Sharma, Ashish K.; Rohrer, Bärbel

doi:10.1016/j.exer.2006.01.014

Cited by 137 publications

(108 citation statements)

References 55 publications

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“…28 Apart from the kinetics of rod death, the nuclear fragmentation of the dying cells may never be detectable where autophagy arises in close parallel with apoptosis, as has been described to occur in the rd1 mouse and in models of light damage. 29 The ultrastructural images here support the possibility that vacuolation and the infiltration of autophagosomes is occurring in the cytoplasm of Nxnl1À/À ONL cells and may explain the absence of TUNEL-positive cells. Furthermore, there are other indications of activity from specific cell-death pathways in the Nxnl1À/À retina.…”

Section: Discussionsupporting

confidence: 56%

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

et al. 2010

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Rod-derived cone viability factor (RdCVF) is a thioredoxin-like protein, which has therapeutic potential for rod-cone dystrophies such as retinitis pigmentosa (RP). Cone loss in rodent models of RP is effectively reduced by RdCVF treatment. In this study, we investigate the physiological role of RdCVF in the retina by analyzing the phenotype of the mouse lacking the RdCVF gene, Nxnl1. Although the mice do not show an obvious developmental defect, an age-related reduction of both cone and rod function and a delay in the dark-adaptation of the retina are recorded by electroretinogram (ERG). This functional change is accompanied by a 17% reduction in cone density and a 20% reduction in thickness of the outer nuclear layer. The transcriptome of the retina reveals early changes in the expression of genes involved in programmed cell death, stress-response and redox-signaling, which is followed by a generalized injury response with increased microglial activation, GFAP, FGF2 and lipid peroxidation levels. Furthermore, cones of the mice lacking Nxnl1 are more sensitive to oxidative stress with a reduction of 65% in the cone flicker ERG amplitude measured under hyperoxic conditions. We show here that the RdCVF gene, in addition to therapeutic properties, has an essential role in photoreceptor maintenance and resistance to retinal oxidative stress.

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Section: Discussionsupporting

confidence: 56%

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

et al. 2010

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“…We have previously confirmed the up-regulation of C1qβ in the rd1 mouse (Rohrer et al 2004) by quantitative real time PCR (QRT-PCR), and extended this analysis to the expression of C1qα , using β-actin and rhodopsin as controls (Table 1). Similar to the expression of C1qβ (Lohr et al 2006), C1qα expression levels peaked in the rd1 mouse retina at P14 and decreased to almost basal levels towards the end of the period of photoreceptor apoptosis (P21). To test the potential role of complement activation in the degenerative process, we combined the rd1 mutation with a C1qα null background.…”

Section: Inactivation Of the Classical Complement Activation Pathwaymentioning

confidence: 69%

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Rohrer

Demos

Frigg

et al. 2007

Experimental Eye Research

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Misregulation of the innate immune response and other immune-related processes have been suggested to play a critical role in the pathogenesis of a number of different neurodegenerative diseases, including age related macular degeneration. In an animal model for photoreceptor degeneration, several genes of the innate and acquired immune system were found to be differentially regulated in the retina during the degenerative process. In addition to this differential regulation of individual genes, we found that in the rd1 retina a significantly higher number of genes involved in immune-related responses were expressed at any given time during the degenerative period. The peak of immune-related gene expression was at postnatal day 14, coinciding with the peak of photoreceptor apoptosis in the rd1 mouse. We directly tested the potential involvement of acquired and innate immune responses in initiation and progression of photoreceptor degeneration by analyzing double mutant animals. Retinal morphology and photoreceptor apoptosis of rd1 mice on a SCID genetic background (no mature T-and B-cells) or in combination with a RAG-1 (no functional B-and T-cells) or a C1qα (no functional classical complement activation pathway) knockout was followed during the degenerative process using light microscopy or TUNEL staining, respectively. Although complement factor C1qα was highly up-regulated in the rd1 retina concomitantly with the degenerative process, lack of this protein did not protect the rd1 retina. Similarly, retinal degeneration and photoreceptor apoptosis appeared to proceed normally in the rd1 mouse lacking functional Band T-cells. Our results suggest that both, the classical complement system of innate immunity and a functional acquired immune response are not essential for the degenerative process in the rd1 mouse retina.

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“…However, to date the role of cathepsins in retinal cell death has received little attention. For instance, an up-regulation in the expression of cathepsins has been detected during photoreceptor degeneration in mutant animals (Sharma and Rohrer, 2004;Doonan et al, 2005;Wenzel et al, 2005;Lohr et al, 2006) and in retinal cells after optic nerve transection and optic nerve crush (Agudo et al, 2009). Moreover, cathepsins B and L are involved in retinal cell death induced by growth factor deprivation in the embryonic mouse retina (Valenciano et al, 2006).…”

Section: Spatiotemporal Expression Of Cathepsin B and D Genes: Relatimentioning

confidence: 99%

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

Bejarano-Escobar

Holguín-Arévalo

Montero

et al. 2011

Developmental Dynamics

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Here, we show a detailed chronotopographical analysis of cathepsin B and D expression during development of the mouse visual system. Both proteases were detected in large rounded/ameboid cells usually located in close relationship with prominent sites of extensive physiological cell death. In concordance with their morphological features and topographical distribution, we demonstrate that expressing cells corresponded with macrophages and microglial precursors. We found that as microglial precursors differentiated the expression of both cathepsins was down-regulated. Of interest, cathepsin B and D transcripts were never observed in degenerating cells. Our findings point to a role for cathepsin D and B in cell debris degradation after apoptotic processes rather than promoting cell death, as proposed for other developmental models. Additionally their pattern of expression suggests a role in the maturation of the microglial precursors.

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Multiple, parallel cellular suicide mechanisms participate in photoreceptor cell death

Cited by 137 publications

References 55 publications

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

Macrophage and microglia ontogeny in the mouse visual system can be traced by the expression of Cathepsins B and D

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