Calpain and PARP Activation during Photoreceptor Cell Death in P23H and S334ter Rhodopsin Mutant Rats

Kaur, Jasvir; Mencl, Stine; Sahaboglu, Ayse; Farinelli, Pietro; Veen, Theo van; Zrenner, Eberhart; Ekström, Per; Paquet-Durand, François; Ueffing, Marius

doi:10.1371/journal.pone.0022181

Cited by 79 publications

(102 citation statements)

References 41 publications

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“…[47][48][49] Bax, Bcl-2, Calpain-2, and Caspase-3 are all critical factors in the photoreceptor apoptotic cascades. [50][51][52] Our study suggests that TES rectifies abnormalities in the apoptotic cascade by altering Bcl-2 and Bax expression, indicating that TES could be developed into a promising and general therapeutic strategy against multiple RP phenotypes. It is especially noteworthy that the expression of Caspase-3, a key executioner of the classical caspase-dependent apoptotic pathway, remains unaffected after TES treatment.…”

Section: Discussionmentioning

confidence: 78%

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Tao

Chen

Liu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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METHODS. N-methyl-N-nitrosourea-administered mice received TES or sham stimulations and were subsequently subjected to electroretinography (ERG), multielectrode array (MEA), and histologic and immunohistochemistry examinations. Quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) analyses were also performed to determine the mRNA levels of Bax, Bcl-2, Calpain-2, Caspase-3, brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF). RESULTS.Amplitudes of ERG b-wave in the TES-treated mice were significantly larger than those in the sham controls (P < 0.01). Microelectrode array examination revealed that the photoreceptors in TES-treated retina were efficiently preserved (P < 0.01). Morphologic measurements showed that the central retina region was more consolidated than the other areas in the TES-treated mice. Together with the disproportionate distribution of immunostaining in retinal flat mounts, these findings indicated that different rescuing kinetics existed among regional photoreceptors. Compared with the sham controls, a significantly increased signal-to-noise ratio was also found in the TES-treated mice (TES100: 2.02 6 1.12; TES200: 4.42 6 1.51; sham: 0.25 6 0.13; P < 0.01). Moreover, qRT-PCR measurements suggested that the altered expression of several apoptotic factors and neurotrophic cytokines was correlated with TES-induced protection.CONCLUSIONS. Regional photoreceptors in the MNU-administered retinas exhibit different sensitivities to TES. Transcorneal electrical stimulation is capable of ameliorating MNUinduced photoreceptor degeneration and rectifying abnormalities in the inner visual signal pathways.Keywords: transcorneal electrical stimulation, therapeutic strategy, retinitis pigmentosa R etinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases characterized by initially impaired dark-adapted sight, progressive deterioration of visual fields, and eventual blindness. 1,2 Currently, the pathologic mechanisms of RP remain poorly understood, and there is no satisfactory therapeutic intervention.3 Retinitis pigmentosa models can be used to explore the pathologic mechanisms underlying this disorder, providing insights into the development of effective therapeutics. The N-methyl-N-nitrosourea (MNU) can pharmacologically induce photoreceptor degeneration. After a single systemic administration, active signs of retinal degeneration, such as decreased outer nuclear layer (ONL) thickness, degraded electroretinogram (ERG) response, and hyperexpressed apoptotic labeling, are indistinct in the MNU-treated retinas due to the selective photoreceptor cell loss. The mechanism underlying MNU-induced photoreceptor death is the principal alkylation of DNA, depending on the action of alkyladenine DNA glycosylase (Aag), an enzyme that removes alkylated bases via cleavage of glycosyl bond connecting base to the sugar phosphate backbone, thus generating abasic sites that can be further processed by the base excision repair machinery.4 N-methyl-N-nitrosourea ...

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Section: Discussionmentioning

confidence: 78%

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Tao

Chen

Liu

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Strong activation of poly(ADP-ribose) polymerase (PARP) has been found in animal models of retinal degeneration with subsequent accumulation of poly(ADP-ribose) (PAR) polymers (PaquetDurand et al, 2007;Kaur et al, 2011). Excessive PARP activation may contribute to caspase-independent photoreceptor death (Paquet-Durand et al, 2007;Kaur et al, 2011).…”

Section: Pde Inhibition Induces Apoptosis In Cultured Porcine Retinamentioning

confidence: 99%

“…Excessive PARP activation may contribute to caspase-independent photoreceptor death (Paquet-Durand et al, 2007;Kaur et al, 2011). To investigate indirectly PARP activity in Zaprinast-treated explants, we performed PAR immunostaining.…”

Section: Pde Inhibition Induces Apoptosis In Cultured Porcine Retinamentioning

confidence: 99%

Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina

Cámara

Sequedo

Gómez‐Pinedo

et al. 2013

Experimental Eye Research

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Inherited retinal degenerations affecting both rod and cone photoreceptors constitute one of the causes of incurable blindness in the developed world. Cyclic guanosine monophosphate (cGMP) is crucial in the phototransduction and, mutations in genes related to its metabolism are responsible for different retinal dystrophies. cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4-5% of the retinitis pigmentosa, a rare form of retinal degeneration. The aim of this study was to evaluate whether pharmacological PDE6 inhibition induced retinal degeneration in cone-enriched cultures of porcine retina similar to that found in murine models. PDE6 inhibition was induced in cone-enriched retinal explants from pigs by Zaprinast. PDE6 inhibition induced cGMP accumulation and triggered retinal degeneration, as determined by TUNEL assay. Western blot analysis and immunostaining indicated that degeneration was accompanied by caspase-3, calpain-2 activation and poly (ADP-ribose) accumulation. Oxidative stress markers, total antioxidant capacity, thiobarbituric acid reactive substances (TBARS) and nitric oxide measurements revealed the presence of oxidative damage. Elevated TNF-alpha and IL-6, as determined by enzyme immunoassay, were also found in cone-enriched retinal explants treated with Zaprinast. Our study suggests that this ex vivo model of retinal degeneration in porcine retina could be an alternative model for therapeutic research into the mechanisms of photoreceptor death in cone-related diseases, thus replacing or reducing animal experiments.

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“…3 For example, DNA damage leading to excessive activation of DNA repair enzymes such as poly-ADP-ribose polymerase (Parp) causes an increase in oxidative stress, mitochondrial damage and subsequent apoptotic cell death in the rd1, P23H and S334ter rodent models of retinal degeneration. 4,5 Similarly, activation of the calcium-dependent cysteine protease calpain can result in an increase in reactive oxygen species (ROS), mitochondrial damage and lysosomal membrane disruption leading to apoptotic cell death in the retina. 5 Recently, the necroptosis mechanism of cell death 6,7 has been implicated in other types of retinal defects such as retinal detachment, 8 retinal ischemia 9 and ocular coloboma.…”

mentioning

confidence: 99%

“…4,5 Similarly, activation of the calcium-dependent cysteine protease calpain can result in an increase in reactive oxygen species (ROS), mitochondrial damage and lysosomal membrane disruption leading to apoptotic cell death in the retina. 5 Recently, the necroptosis mechanism of cell death 6,7 has been implicated in other types of retinal defects such as retinal detachment, 8 retinal ischemia 9 and ocular coloboma. 10 In these cases, either cell death was delayed by the inhibitor necrostatin-1, which targets receptor interacting protein kinase 1 (RIP1) 11 or the presence of elevated receptor interacting protein kinase 3 (RIP3) was detected, suggesting that cell death in the retina maybe dependent on these key regulators of necroptosis.…”

mentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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Calpain and PARP Activation during Photoreceptor Cell Death in P23H and S334ter Rhodopsin Mutant Rats

Cited by 79 publications

References 41 publications

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)–Induced Protective Effects on N-Methyl-N-Nitrosourea–Treated Retinas

Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

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