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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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Heat map representing metabolic activities in different RD models.The RD models were grouped according to the peak of degeneration, the cell type affected by the mutation (rod, cone, RPE), and species (mouse, rat). The number of TUNEL-positive cells in each model was normalized to 100, expressed as logarithm, and compared with the number of positively labelled cells for each marker. The heat map clearly illustrates the prevalence of non-apoptotic vs. apoptotic cell death in 9 out of 10 RD models. The S334ter rhodopsin mutant was unique, showing concurrent activation of both cell death pathways. n.p.:  positive. See also Table S1 and S2.
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pone-0112142-g005: Heat map representing metabolic activities in different RD models.The RD models were grouped according to the peak of degeneration, the cell type affected by the mutation (rod, cone, RPE), and species (mouse, rat). The number of TUNEL-positive cells in each model was normalized to 100, expressed as logarithm, and compared with the number of positively labelled cells for each marker. The heat map clearly illustrates the prevalence of non-apoptotic vs. apoptotic cell death in 9 out of 10 RD models. The S334ter rhodopsin mutant was unique, showing concurrent activation of both cell death pathways. n.p.: positive. See also Table S1 and S2.

Mentions: To compare the different cell death processes, we related the numbers of positive cells detected by each individual assay to the numbers of TUNEL positive cells. To match the various RD models and their very different degeneration kinetics with each other, all values were expressed as logarithm to base 10. Since the TUNEL values were defined as 100%, its logarithm was 2. This comparative analysis highlighted the fact that non-apoptotic processes were clearly dominant for photoreceptor degeneration in all RD models (Figure 5). This was also true for the S334ter model which, interestingly, showed the additional involvement of apoptotic cell death. We also analysed the relative contribution of apoptotic and non-apoptotic processes to developmental cell death in wild-type retina (P13-P42). Here, the relative contributions of apoptotic and non-apoptotic cell death mechanisms appeared to be equally important (Figure S3).


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)

Heat map representing metabolic activities in different RD models.The RD models were grouped according to the peak of degeneration, the cell type affected by the mutation (rod, cone, RPE), and species (mouse, rat). The number of TUNEL-positive cells in each model was normalized to 100, expressed as logarithm, and compared with the number of positively labelled cells for each marker. The heat map clearly illustrates the prevalence of non-apoptotic vs. apoptotic cell death in 9 out of 10 RD models. The S334ter rhodopsin mutant was unique, showing concurrent activation of both cell death pathways. n.p.:  positive. See also Table S1 and S2.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112142-g005: Heat map representing metabolic activities in different RD models.The RD models were grouped according to the peak of degeneration, the cell type affected by the mutation (rod, cone, RPE), and species (mouse, rat). The number of TUNEL-positive cells in each model was normalized to 100, expressed as logarithm, and compared with the number of positively labelled cells for each marker. The heat map clearly illustrates the prevalence of non-apoptotic vs. apoptotic cell death in 9 out of 10 RD models. The S334ter rhodopsin mutant was unique, showing concurrent activation of both cell death pathways. n.p.: positive. See also Table S1 and S2.
Mentions: To compare the different cell death processes, we related the numbers of positive cells detected by each individual assay to the numbers of TUNEL positive cells. To match the various RD models and their very different degeneration kinetics with each other, all values were expressed as logarithm to base 10. Since the TUNEL values were defined as 100%, its logarithm was 2. This comparative analysis highlighted the fact that non-apoptotic processes were clearly dominant for photoreceptor degeneration in all RD models (Figure 5). This was also true for the S334ter model which, interestingly, showed the additional involvement of apoptotic cell death. We also analysed the relative contribution of apoptotic and non-apoptotic processes to developmental cell death in wild-type retina (P13-P42). Here, the relative contributions of apoptotic and non-apoptotic cell death mechanisms appeared to be equally important (Figure S3).

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