Attenuation of Vision Loss and Delay in Apoptosis of Photoreceptors Induced by Proinsulin in a Mouse Model of Retinitis Pigmentosa

Corrochano, Silvia; Barhoum, R.; Boya, Patricia; Arroba, Ana I.; Rodríguez-Muela, Natalia; Gómez‐Vicente, Violeta; Bosch, Fátima; Pablo, Flora de; Villa, Pedro de la; Rosa, Enrique J. de la

doi:10.1167/iovs.08-2182

Cited by 49 publications

(69 citation statements)

References 41 publications

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“…Cell death peaks in the rd10 mouse around P25. 24,25 As autophagy is one of the major intracellular stress responses, we analysed the lipidation of the autophagosomal marker LC3 in Wt and rd10 retinas at different stages. Days before the peak of cell death, at P20, levels of the lipidated form of LC3 (LC3-II) were decreased in rd10 versus Wt mice, whereas those of the autophagy substrate p62 were increased (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…23,24 This mutation results in reduced enzymatic function leading to increased cGMP and rod cell death, peaking around postnatal day 25 (P25), with only residual vision remaining after P30. 24,25 Here we show that rd10 mice exhibit massive intracellular calcium accumulation and m-calpain (calpain-2) activation at early ages, before the peak of photoreceptor cell death, that correlate with the blockade of autophagic flux. Moreover, we demonstrate an increase in cathepsin B activity in the cytoplasm of rd10 photoreceptors that correlates with the activation of DNAse II-dependent cell death.…”

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confidence: 90%

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Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

et al. 2014

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Retinitis pigmentosa is a group of hereditary retinal dystrophies that normally result in photoreceptor cell death and vision loss both in animal models and in affected patients. The rd10 mouse, which carries a missense mutation in the Pde6b gene, has been used to characterize the underlying pathophysiology and develop therapies for this devastating and incurable disease. Here we show that increased photoreceptor cell death in the rd10 mouse retina is associated with calcium overload and calpain activation, both of which are observed before the appearance of signs of cell degeneration. These changes are accompanied by an increase in the activity of the lysosomal protease cathepsin B in the cytoplasm of photoreceptor cells, and a reduced colocalization of cathepsin B with lysosomal markers, suggesting that lysosomal membrane permeabilization occurs before the peak of cell death. Moreover, expression of the autophagosomal marker LC3-II (lipidated form of LC3) is reduced and autophagy flux is blocked in rd10 retinas before the onset of photoreceptor cell death. Interestingly, we found that cell death is increased by the induction of autophagy with rapamycin and inhibited by calpain and cathepsin inhibitors, both ex vivo and in vivo. Taken together, these data suggest that calpain-mediated lysosomal membrane permeabilization underlies the lysosomal dysfunction and downregulation of autophagy associated with photoreceptor cell death.

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Section: Resultsmentioning

confidence: 99%

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confidence: 90%

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

et al. 2014

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“…35 In these mice, photoreceptor death begins at postnatal day P20, and is accompanied by molecular alterations in photoreceptor cells, including increased levels of oxidative stress and massive calcium accumulation. 36 To determine whether mitochondrial levels are altered in these mice, we isolated retinas from WT and Pde6b rd10 mice on P20 and P30 and evaluated MTDR fluorescence levels by flow cytometry. MTDR fluorescence levels were increased at both time points in Pde6b rd10 versus WT animals (Fig.…”

Section: Determination Of Mitophagy In Primary Cells and Tissues Usinmentioning

confidence: 99%

New method to assess mitophagy flux by flow cytometry

et al. 2015

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“…Although there is presently no cure for RP, substantial progress has been made to elucidate the genetics and cell biology of these disorders. In particular, rod photoreceptor death in RP is largely thought to occur by apoptosis (2)(3)(4)(5), although nonapoptotic mechanisms have also been proposed (5).…”

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Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

Strettoi

Gargini

Novelli

et al. 2010

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

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Retinitis pigmentosa (RP) is a genetic disease causing progressive apoptotic death of photoreceptors and, ultimately, incurable blindness. Using the retinal degeneration 10 (rd10) mouse model of RP, we investigated the role of ceramide, a proapoptotic sphingolipid, in retinal degeneration. We also tested the possibility that photoreceptor loss can be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. Retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Single intraocular injections of myriocin, a powerful inhibitor of serine palmitoyl-CoA transferase, the ratelimiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Short-term noninvasive treatment lowered retinal ceramide in a manner similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting transcorneal drug administration. Prolonged treatment (10-20 d) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Transcorneal administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies.sphingolipid | apoptosis | electroretinography | morphology

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Attenuation of Vision Loss and Delay in Apoptosis of Photoreceptors Induced by Proinsulin in a Mouse Model of Retinitis Pigmentosa

Abstract: These results provide a new basis for possible therapies to counteract retinitis pigmentosa and a new tool to characterize the mechanisms involved in the progress of retinal neurodegeneration.

Cited by 49 publications

References 41 publications

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

New method to assess mitophagy flux by flow cytometry

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

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