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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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Progression of cell death in inherited RD models.Depending on the causative genetic insult, the temporal development of retinal degeneration is highly variable in the different animal models. The quantification of dying, TUNEL-positive photoreceptor cells in the outer nuclear layer (ONL) allowed determination of the evolution and the peak of photoreceptor death for each of these animal models (A). The peak was taken as reference point for the ensuing analysis of cell death mechanisms. The bar graph (B) shows a comparison of maximum peak heights for all ten RD models studied. Note the different scales in line graphs. Values are mean ± SEM from at least three different animals. See also Table S1 and S2.
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pone-0112142-g002: Progression of cell death in inherited RD models.Depending on the causative genetic insult, the temporal development of retinal degeneration is highly variable in the different animal models. The quantification of dying, TUNEL-positive photoreceptor cells in the outer nuclear layer (ONL) allowed determination of the evolution and the peak of photoreceptor death for each of these animal models (A). The peak was taken as reference point for the ensuing analysis of cell death mechanisms. The bar graph (B) shows a comparison of maximum peak heights for all ten RD models studied. Note the different scales in line graphs. Values are mean ± SEM from at least three different animals. See also Table S1 and S2.

Mentions: To study the cell death mechanisms governing RD, we first performed a detailed analysis of the temporal progression of the degeneration for each of the 10 animal models used (Figure 1). We used the TUNEL assay to label dying cells at different postnatal ages and quantified the percentages of TUNEL-positive cells in the outer nuclear layer (ONL), i.e. the photoreceptor layer (Figure 2).


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)

Progression of cell death in inherited RD models.Depending on the causative genetic insult, the temporal development of retinal degeneration is highly variable in the different animal models. The quantification of dying, TUNEL-positive photoreceptor cells in the outer nuclear layer (ONL) allowed determination of the evolution and the peak of photoreceptor death for each of these animal models (A). The peak was taken as reference point for the ensuing analysis of cell death mechanisms. The bar graph (B) shows a comparison of maximum peak heights for all ten RD models studied. Note the different scales in line graphs. Values are mean ± SEM from at least three different animals. See also Table S1 and S2.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112142-g002: Progression of cell death in inherited RD models.Depending on the causative genetic insult, the temporal development of retinal degeneration is highly variable in the different animal models. The quantification of dying, TUNEL-positive photoreceptor cells in the outer nuclear layer (ONL) allowed determination of the evolution and the peak of photoreceptor death for each of these animal models (A). The peak was taken as reference point for the ensuing analysis of cell death mechanisms. The bar graph (B) shows a comparison of maximum peak heights for all ten RD models studied. Note the different scales in line graphs. Values are mean ± SEM from at least three different animals. See also Table S1 and S2.
Mentions: To study the cell death mechanisms governing RD, we first performed a detailed analysis of the temporal progression of the degeneration for each of the 10 animal models used (Figure 1). We used the TUNEL assay to label dying cells at different postnatal ages and quantified the percentages of TUNEL-positive cells in the outer nuclear layer (ONL), i.e. the photoreceptor layer (Figure 2).

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