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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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RD animal models used and their genetic defects.The cartoon illustrates the anatomical localization and metabolic consequences of the causative genetic mutations in the ten different RD animal models used in this study. RD causing mutations in these animal models interfere with the various stages of the phototransduction cascade, from the 11-cis-retinal recycling enzyme RPE65 (Rpe65 KO), via the light-sensitive Rhodopsin (Rho KO, P23H, S334ter), cGMP-hydrolyzing phosphodiesterase-6 (PDE6; rd1, rd10, cpfl1), the structural protein Peripherin (Prph2; rd2), to the cyclic-nucleotide-gated (CNG; Cngb1 KO, Cnga3 KO) channel that allows for Ca2+-influx.
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pone-0112142-g001: RD animal models used and their genetic defects.The cartoon illustrates the anatomical localization and metabolic consequences of the causative genetic mutations in the ten different RD animal models used in this study. RD causing mutations in these animal models interfere with the various stages of the phototransduction cascade, from the 11-cis-retinal recycling enzyme RPE65 (Rpe65 KO), via the light-sensitive Rhodopsin (Rho KO, P23H, S334ter), cGMP-hydrolyzing phosphodiesterase-6 (PDE6; rd1, rd10, cpfl1), the structural protein Peripherin (Prph2; rd2), to the cyclic-nucleotide-gated (CNG; Cngb1 KO, Cnga3 KO) channel that allows for Ca2+-influx.

Mentions: In the present study, we asked the question whether there was a common mechanism governing photoreceptor cell death independent of the initial causative genetic defect, since this could open up for broadly applicable therapies. To address the heterogeneity of hereditary photoreceptor degeneration, we employed ten different animal models RD (Figure 1), eight models for primary rod degeneration, as seen in autosomal dominant RP (P23H and S334ter transgenic rats) and autosomal recessive RP (rd1, rd2, rd10, Cngb1 KO, Rho KO mice), as well as in LCA (Rpe65 KO mice). In addition, we also included two animal models for primary cone death (cpfl1, Cnga3 KO mice).


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)

RD animal models used and their genetic defects.The cartoon illustrates the anatomical localization and metabolic consequences of the causative genetic mutations in the ten different RD animal models used in this study. RD causing mutations in these animal models interfere with the various stages of the phototransduction cascade, from the 11-cis-retinal recycling enzyme RPE65 (Rpe65 KO), via the light-sensitive Rhodopsin (Rho KO, P23H, S334ter), cGMP-hydrolyzing phosphodiesterase-6 (PDE6; rd1, rd10, cpfl1), the structural protein Peripherin (Prph2; rd2), to the cyclic-nucleotide-gated (CNG; Cngb1 KO, Cnga3 KO) channel that allows for Ca2+-influx.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112142-g001: RD animal models used and their genetic defects.The cartoon illustrates the anatomical localization and metabolic consequences of the causative genetic mutations in the ten different RD animal models used in this study. RD causing mutations in these animal models interfere with the various stages of the phototransduction cascade, from the 11-cis-retinal recycling enzyme RPE65 (Rpe65 KO), via the light-sensitive Rhodopsin (Rho KO, P23H, S334ter), cGMP-hydrolyzing phosphodiesterase-6 (PDE6; rd1, rd10, cpfl1), the structural protein Peripherin (Prph2; rd2), to the cyclic-nucleotide-gated (CNG; Cngb1 KO, Cnga3 KO) channel that allows for Ca2+-influx.
Mentions: In the present study, we asked the question whether there was a common mechanism governing photoreceptor cell death independent of the initial causative genetic defect, since this could open up for broadly applicable therapies. To address the heterogeneity of hereditary photoreceptor degeneration, we employed ten different animal models RD (Figure 1), eight models for primary rod degeneration, as seen in autosomal dominant RP (P23H and S334ter transgenic rats) and autosomal recessive RP (rd1, rd2, rd10, Cngb1 KO, Rho KO mice), as well as in LCA (Rpe65 KO mice). In addition, we also included two animal models for primary cone death (cpfl1, Cnga3 KO mice).

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