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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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Apoptosis in the retina is restricted to the S334ter rat model.The analysis of BAX expression, mitochondrial cytochrome c release, activation of caspase-9 and -3 shows essentially no positive detection in 9 out of 10 animal models for hereditary retinal degeneration. The notable exception was the S334ter transgenic rat which harbours a mutation in the rhodopsin gene leading to a truncated protein and in which many photoreceptors were positive for apoptosis. In all other animal models, while there were cells displaying clear evidence for apoptosis, their numbers were within the wild-type levels, indicating that this was related to physiological, developmental cell death, which is characteristic for the postnatal rodent retina. Importantly, the numbers of apoptotic cells did not match the numbers of mutation-induced dying cells as evidenced by the TUNEL assay. Scale bar 20 µm.
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pone-0112142-g003: Apoptosis in the retina is restricted to the S334ter rat model.The analysis of BAX expression, mitochondrial cytochrome c release, activation of caspase-9 and -3 shows essentially no positive detection in 9 out of 10 animal models for hereditary retinal degeneration. The notable exception was the S334ter transgenic rat which harbours a mutation in the rhodopsin gene leading to a truncated protein and in which many photoreceptors were positive for apoptosis. In all other animal models, while there were cells displaying clear evidence for apoptosis, their numbers were within the wild-type levels, indicating that this was related to physiological, developmental cell death, which is characteristic for the postnatal rodent retina. Importantly, the numbers of apoptotic cells did not match the numbers of mutation-induced dying cells as evidenced by the TUNEL assay. Scale bar 20 µm.

Mentions: We looked for increased expression, localization, or activation of Bcl-2–associated X protein (BAX), cytochrome c, cleaved, activated caspase-9 and -3 (Figure 3, quantification in Table S1 and S2). Increases in these apoptotic markers were found only in the S334ter model when compared to the corresponding wild-type.


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)

Apoptosis in the retina is restricted to the S334ter rat model.The analysis of BAX expression, mitochondrial cytochrome c release, activation of caspase-9 and -3 shows essentially no positive detection in 9 out of 10 animal models for hereditary retinal degeneration. The notable exception was the S334ter transgenic rat which harbours a mutation in the rhodopsin gene leading to a truncated protein and in which many photoreceptors were positive for apoptosis. In all other animal models, while there were cells displaying clear evidence for apoptosis, their numbers were within the wild-type levels, indicating that this was related to physiological, developmental cell death, which is characteristic for the postnatal rodent retina. Importantly, the numbers of apoptotic cells did not match the numbers of mutation-induced dying cells as evidenced by the TUNEL assay. Scale bar 20 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112142-g003: Apoptosis in the retina is restricted to the S334ter rat model.The analysis of BAX expression, mitochondrial cytochrome c release, activation of caspase-9 and -3 shows essentially no positive detection in 9 out of 10 animal models for hereditary retinal degeneration. The notable exception was the S334ter transgenic rat which harbours a mutation in the rhodopsin gene leading to a truncated protein and in which many photoreceptors were positive for apoptosis. In all other animal models, while there were cells displaying clear evidence for apoptosis, their numbers were within the wild-type levels, indicating that this was related to physiological, developmental cell death, which is characteristic for the postnatal rodent retina. Importantly, the numbers of apoptotic cells did not match the numbers of mutation-induced dying cells as evidenced by the TUNEL assay. Scale bar 20 µm.
Mentions: We looked for increased expression, localization, or activation of Bcl-2–associated X protein (BAX), cytochrome c, cleaved, activated caspase-9 and -3 (Figure 3, quantification in Table S1 and S2). Increases in these apoptotic markers were found only in the S334ter model when compared to the corresponding wild-type.

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