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Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration.

Arango-Gonzalez B, Trifunović D, Sahaboglu A, Kranz K, Michalakis S, Farinelli P, Koch S, Koch F, Cottet S, Janssen-Bienhold U, Dedek K, Biel M, Zrenner E, Euler T, Ekström P, Ueffing M, Paquet-Durand F - PLoS ONE (2014)

Bottom Line: We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death.We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance.Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.

View Article: PubMed Central - PubMed

Affiliation: Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.

ABSTRACT
Cell death in neurodegenerative diseases is often thought to be governed by apoptosis; however, an increasing body of evidence suggests the involvement of alternative cell death mechanisms in neuronal degeneration. We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death. We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance. Hallmark features of this pathway are activation of histone deacetylase, poly-ADP-ribose-polymerase, and calpain, as well as accumulation of cyclic guanosine monophosphate and poly-ADP-ribose. Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.

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Cell death in hereditary retinal degeneration is predominantly non-apoptotic.In 10 out of 10 animal models for hereditary retinal degeneration, large numbers of photoreceptors display cGMP accumulation, HDAC and PARP activity, PAR accumulation, and calpain activity, respectively. Intriguingly, these non-apoptotic markers are prominent even in the S334ter retina, concomitant with this also showing signs of apoptosis. This suggests that in S334ter retina two different cell death mechanisms may run in parallel while in all other studied RD models the mutation-induced cell death followed a non-apoptotic mechanism. Scale bar 20 µm.
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pone-0112142-g004: Cell death in hereditary retinal degeneration is predominantly non-apoptotic.In 10 out of 10 animal models for hereditary retinal degeneration, large numbers of photoreceptors display cGMP accumulation, HDAC and PARP activity, PAR accumulation, and calpain activity, respectively. Intriguingly, these non-apoptotic markers are prominent even in the S334ter retina, concomitant with this also showing signs of apoptosis. This suggests that in S334ter retina two different cell death mechanisms may run in parallel while in all other studied RD models the mutation-induced cell death followed a non-apoptotic mechanism. Scale bar 20 µm.

Mentions: cGMP accumulation in phosphodiesterase-6 mutants (rd1, rd10, cpfl1) is a direct consequence of the lack of phosphodiesterase activity that normally hydrolyses cGMP. Surprisingly, significant cGMP accumulation was observed also in all other analysed mouse and rat models (Figure 4, Table S1) except for Rpe65 KO retina, where the initial causative defect does not reside in photoreceptors themselves but in retinal pigment epithelial cells. However, the patterns of cGMP accumulation varied between different RD models (Figure 4). In the case of rd1, rd10, rd2, Cnga3 and cpfl1 cGMP was visible in cell bodies as well as in photoreceptor inner/outer segments, whereas in Cngb1 KO retina the signal was more prominent in inner/outer segments. For methodological reasons, we only quantified cGMP positive cell bodies. As a consequence, most likely the true number of photoreceptors showing elevated cGMP levels is higher in Cngb1 KO retina than assessed here. P23H and S334ter rat retinas were characterized by diffuse cGMP accumulation in the ONL, contrary to Rho KO mice in which only very few nuclei were cGMP-positive.


Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration.

Arango-Gonzalez B, Trifunović D, Sahaboglu A, Kranz K, Michalakis S, Farinelli P, Koch S, Koch F, Cottet S, Janssen-Bienhold U, Dedek K, Biel M, Zrenner E, Euler T, Ekström P, Ueffing M, Paquet-Durand F - PLoS ONE (2014)

Cell death in hereditary retinal degeneration is predominantly non-apoptotic.In 10 out of 10 animal models for hereditary retinal degeneration, large numbers of photoreceptors display cGMP accumulation, HDAC and PARP activity, PAR accumulation, and calpain activity, respectively. Intriguingly, these non-apoptotic markers are prominent even in the S334ter retina, concomitant with this also showing signs of apoptosis. This suggests that in S334ter retina two different cell death mechanisms may run in parallel while in all other studied RD models the mutation-induced cell death followed a non-apoptotic mechanism. Scale bar 20 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230983&req=5

pone-0112142-g004: Cell death in hereditary retinal degeneration is predominantly non-apoptotic.In 10 out of 10 animal models for hereditary retinal degeneration, large numbers of photoreceptors display cGMP accumulation, HDAC and PARP activity, PAR accumulation, and calpain activity, respectively. Intriguingly, these non-apoptotic markers are prominent even in the S334ter retina, concomitant with this also showing signs of apoptosis. This suggests that in S334ter retina two different cell death mechanisms may run in parallel while in all other studied RD models the mutation-induced cell death followed a non-apoptotic mechanism. Scale bar 20 µm.
Mentions: cGMP accumulation in phosphodiesterase-6 mutants (rd1, rd10, cpfl1) is a direct consequence of the lack of phosphodiesterase activity that normally hydrolyses cGMP. Surprisingly, significant cGMP accumulation was observed also in all other analysed mouse and rat models (Figure 4, Table S1) except for Rpe65 KO retina, where the initial causative defect does not reside in photoreceptors themselves but in retinal pigment epithelial cells. However, the patterns of cGMP accumulation varied between different RD models (Figure 4). In the case of rd1, rd10, rd2, Cnga3 and cpfl1 cGMP was visible in cell bodies as well as in photoreceptor inner/outer segments, whereas in Cngb1 KO retina the signal was more prominent in inner/outer segments. For methodological reasons, we only quantified cGMP positive cell bodies. As a consequence, most likely the true number of photoreceptors showing elevated cGMP levels is higher in Cngb1 KO retina than assessed here. P23H and S334ter rat retinas were characterized by diffuse cGMP accumulation in the ONL, contrary to Rho KO mice in which only very few nuclei were cGMP-positive.

Bottom Line: We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death.We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance.Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.

View Article: PubMed Central - PubMed

Affiliation: Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.

ABSTRACT
Cell death in neurodegenerative diseases is often thought to be governed by apoptosis; however, an increasing body of evidence suggests the involvement of alternative cell death mechanisms in neuronal degeneration. We studied retinal neurodegeneration using 10 different animal models, covering all major groups of hereditary human blindness (rd1, rd2, rd10, Cngb1 KO, Rho KO, S334ter, P23H, Cnga3 KO, cpfl1, Rpe65 KO), by investigating metabolic processes relevant for different forms of cell death. We show that apoptosis plays only a minor role in the inherited forms of retinal neurodegeneration studied, where instead, a non-apoptotic degenerative mechanism common to all mutants is of major importance. Hallmark features of this pathway are activation of histone deacetylase, poly-ADP-ribose-polymerase, and calpain, as well as accumulation of cyclic guanosine monophosphate and poly-ADP-ribose. Our work thus demonstrates the prevalence of alternative cell death mechanisms in inherited retinal degeneration and provides a rational basis for the design of mutation-independent treatments.

Show MeSH
Related in: MedlinePlus