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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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Two routes to cell death.Classical apoptosis, such as it occurs in S334ter transgenic photoreceptors, involves a mutation-induced up-regulation and translocation of BAX protein to form the mitochondrial permeability transition pore (MPTP). This leads to leakage of cytochrome c from the mitochondria to the cytoplasm, where it combines with apoptotic protease activating factor (APAF) and caspase-9 to form the apoptosome, which in turn activates down-stream executioner caspases, including caspase-3. In 9/10 RD animal models investigated here, photoreceptor death followed a different route: mutation-induced up-regulation of cGMP on the one hand causes activation of the CNG channel, leading to Ca2+ influx and calpain activation. On the other hand cGMP-dependent activation of protein kinase G (PKG) is associated with histone deacetylase (HDAC) and poly-ADP-ribose-polymerase (PARP) activation. Importantly, this alternative, non-apoptotic cell death mechanism offers a number of novel targets for neuroprotection of photoreceptors.
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pone-0112142-g006: Two routes to cell death.Classical apoptosis, such as it occurs in S334ter transgenic photoreceptors, involves a mutation-induced up-regulation and translocation of BAX protein to form the mitochondrial permeability transition pore (MPTP). This leads to leakage of cytochrome c from the mitochondria to the cytoplasm, where it combines with apoptotic protease activating factor (APAF) and caspase-9 to form the apoptosome, which in turn activates down-stream executioner caspases, including caspase-3. In 9/10 RD animal models investigated here, photoreceptor death followed a different route: mutation-induced up-regulation of cGMP on the one hand causes activation of the CNG channel, leading to Ca2+ influx and calpain activation. On the other hand cGMP-dependent activation of protein kinase G (PKG) is associated with histone deacetylase (HDAC) and poly-ADP-ribose-polymerase (PARP) activation. Importantly, this alternative, non-apoptotic cell death mechanism offers a number of novel targets for neuroprotection of photoreceptors.

Mentions: Together with other earlier data [8], [16], [42], [43] our present findings prompt us to propose a potential pathway for cGMP-induced cell death: Elevated levels of cGMP activate CNG channels and/or PKG to cause excessive Ca2+-influx and protein phosphorylation, respectively. As a possible consequence of the latter, PKG dependent phosphorylation could trigger HDAC activation [44], down-stream of which PARP can be activated [15]. Ca2+-influx might on the other hand, and in parallel, cause calpain activation [13], [35]. Both routes (Figure 6) act in unison to drive a photoreceptor cell to its demise, but, surprisingly, this alternative form of cGMP-induced cell death appears to be 4–6 times slower than apoptosis [41]. Importantly, the presence of this pathway and the connections between the different metabolic processes were confirmed by interventional experiments in the rd1 mouse demonstrating the neuroprotective effects of inhibition of PKG [22], calpain [13], PARP [12], and HDAC [15].


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)

Two routes to cell death.Classical apoptosis, such as it occurs in S334ter transgenic photoreceptors, involves a mutation-induced up-regulation and translocation of BAX protein to form the mitochondrial permeability transition pore (MPTP). This leads to leakage of cytochrome c from the mitochondria to the cytoplasm, where it combines with apoptotic protease activating factor (APAF) and caspase-9 to form the apoptosome, which in turn activates down-stream executioner caspases, including caspase-3. In 9/10 RD animal models investigated here, photoreceptor death followed a different route: mutation-induced up-regulation of cGMP on the one hand causes activation of the CNG channel, leading to Ca2+ influx and calpain activation. On the other hand cGMP-dependent activation of protein kinase G (PKG) is associated with histone deacetylase (HDAC) and poly-ADP-ribose-polymerase (PARP) activation. Importantly, this alternative, non-apoptotic cell death mechanism offers a number of novel targets for neuroprotection of photoreceptors.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112142-g006: Two routes to cell death.Classical apoptosis, such as it occurs in S334ter transgenic photoreceptors, involves a mutation-induced up-regulation and translocation of BAX protein to form the mitochondrial permeability transition pore (MPTP). This leads to leakage of cytochrome c from the mitochondria to the cytoplasm, where it combines with apoptotic protease activating factor (APAF) and caspase-9 to form the apoptosome, which in turn activates down-stream executioner caspases, including caspase-3. In 9/10 RD animal models investigated here, photoreceptor death followed a different route: mutation-induced up-regulation of cGMP on the one hand causes activation of the CNG channel, leading to Ca2+ influx and calpain activation. On the other hand cGMP-dependent activation of protein kinase G (PKG) is associated with histone deacetylase (HDAC) and poly-ADP-ribose-polymerase (PARP) activation. Importantly, this alternative, non-apoptotic cell death mechanism offers a number of novel targets for neuroprotection of photoreceptors.
Mentions: Together with other earlier data [8], [16], [42], [43] our present findings prompt us to propose a potential pathway for cGMP-induced cell death: Elevated levels of cGMP activate CNG channels and/or PKG to cause excessive Ca2+-influx and protein phosphorylation, respectively. As a possible consequence of the latter, PKG dependent phosphorylation could trigger HDAC activation [44], down-stream of which PARP can be activated [15]. Ca2+-influx might on the other hand, and in parallel, cause calpain activation [13], [35]. Both routes (Figure 6) act in unison to drive a photoreceptor cell to its demise, but, surprisingly, this alternative form of cGMP-induced cell death appears to be 4–6 times slower than apoptosis [41]. Importantly, the presence of this pathway and the connections between the different metabolic processes were confirmed by interventional experiments in the rd1 mouse demonstrating the neuroprotective effects of inhibition of PKG [22], calpain [13], PARP [12], and HDAC [15].

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