Ceramide Induces the Death of Retina Photoreceptors Through Activation of Parthanatos

Spalm, Facundo H. Prado; Vera, Marcela S.; Dibo, Marcos; Simón, M. Victoria; Politi, Luis E.; Rotstein, Nora P.

doi:10.1007/s12035-018-1402-4

Cited by 34 publications

(15 citation statements)

References 84 publications

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“…Cer has also been shown to activate necroptosis, which is triggered by high levels of C16:0-Cer (89). Recent evidence also establishes that Cer induces Parthanatos, causing neuroblastoma and photoreceptor cell death (55,90).…”

Section: Ceramide: the Death Orchestratormentioning

confidence: 99%

“…Cer has been shown to trigger photoreceptor degeneration in vitro by activating PARP-1, thus increasing the levels of polyADP ribose (PAR) polymers and promoting translocation of apoptosis inducing factor (AIF) from mitochondria to the nuclei of photoreceptors, which are established features of Parthanatos. Inhibition of PARP-1 activation protects these neurons from Cer-induced death (55). Interestingly, activation of PARP-in RP animal models (299)(300)(301).…”

Section: Retinitis Pigmentosa: Is Cer a Common Activator?mentioning

confidence: 99%

“…Cer has been a prime suspect in the cellular "crime scene" ever since its key roles in controlling cell death and growth arrest were uncovered over four decades ago. This bioactive sphingolipid is involved in senescence, inhibition of cell proliferation, inflammation, and in the induction of several pathways of cell death, including apoptosis, autophagy, and parthanatos (15,49,54,55). Cer-mediated cell death is frequently associated with mitochondrial dysfunction (56)(57)(58)(59).…”

Section: Ceramide: the Death Orchestratormentioning

confidence: 99%

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Sphingolipids as critical players in retinal physiology and pathology

Simón

Basu

Qaladize

et al. 2021

Journal of Lipid Research

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Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.

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Section: Ceramide: the Death Orchestratormentioning

confidence: 99%

Section: Retinitis Pigmentosa: Is Cer a Common Activator?mentioning

confidence: 99%

Section: Ceramide: the Death Orchestratormentioning

confidence: 99%

See 1 more Smart Citation

Sphingolipids as critical players in retinal physiology and pathology

Simón

Basu

Qaladize

et al. 2021

Journal of Lipid Research

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“…Hence, CCI in adult mice may trigger neuronal cell death phenotypes other than intrinsic apoptosis such as those involving calpains 78 . Our data show that mithramycin has more limited effects in calpain-dependent neuronal cell death including that induced by ceramide 79 . Thus, while mithramycin may still attenuate some p53-dependent intrinsic apoptotic program elements, including BH3-only molecules, downstream cell death proteases and caspase-independent mechanisms as well as c-Jun activation, the narrower nature of these effects and relatively modest role played by the caspase-dependent portion of this cascade will likely reduce the neuroprotective therapeutic effect of mithramycin in acute TBI.…”

Section: Discussionmentioning

confidence: 70%

Mithramycin selectively attenuates DNA-damage-induced neuronal cell death

et al. 2020

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DNA damage triggers cell death mechanisms contributing to neuronal loss and cognitive decline in neurological disorders, including traumatic brain injury (TBI), and as a side effect of chemotherapy. Mithramycin, which competitively targets chromatin-binding sites of specificity protein 1 (Sp1), was used to examine previously unexplored neuronal cell death regulatory mechanisms via rat primary neurons in vitro and after TBI in mice (males). In primary neurons exposed to DNA-damage-inducing chemotherapy drugs in vitro we showed that DNA breaks sequentially initiate DNA-damage responses, including phosphorylation of ATM, H2AX and tumor protein 53 (p53), transcriptional activation of pro-apoptotic BH3-only proteins, and mitochondrial outer membrane permeabilization (MOMP), activating caspase-dependent and caspase-independent intrinsic apoptosis. Mithramycin was highly neuroprotective in DNA-damage-dependent neuronal cell death, inhibiting chemotherapeutic-induced cell death cascades downstream of ATM and p53 phosphorylation/activation but upstream of p53-induced expression of pro-apoptotic molecules. Mithramycin reduced neuronal upregulation of BH3-only proteins and mitochondrial dysfunction, attenuated caspase-3/7 activation and caspase substrates’ cleavage, and limited c-Jun activation. Chromatin immunoprecipitation indicated that mithramycin attenuates Sp1 binding to pro-apoptotic gene promoters without altering p53 binding suggesting it acts by removing cofactors required for p53 transactivation. In contrast, the DNA-damage-independent neuronal death models displayed caspase initiation in the absence of p53/BH3 activation and were not protected even when mithramycin reduced caspase activation. Interestingly, experimental TBI triggers a multiplicity of neuronal death mechanisms. Although markers of DNA-damage/p53-dependent intrinsic apoptosis are detected acutely in the injured cortex and are attenuated by mithramycin, these processes may play a reduced role in early neuronal death after TBI, as caspase-dependent mechanisms are repressed in mature neurons while other, mithramycin-resistant mechanisms are active. Our data suggest that Sp1 is required for p53-mediated transactivation of neuronal pro-apoptotic molecules and that mithramycin may attenuate neuronal cell death in conditions predominantly involving DNA-damage-induced p53-dependent intrinsic apoptosis.

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“…Increased ceramide has been shown to lead to apoptosis through mitochondrial oxidative stress in neuroblastoma cells (Czubowicz and Strosznajder, 2014). Using cultured retinal neurons, exogenous ceramide was shown to decrease mitochondrial membrane potential (Prado Spalm et al, 2019). Also, NOX inhibition eased the oxidative stress resulted from TNF-α-induced ceramide production in SH-SY5Y cells (Barth et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Tzou

et al. 2020

Preprint

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Dihydroceramide and NeurodegenerationTzou et al. Highlights  Deficiency in dihydroceramide (dhCer) desaturase induces cytoplasmic ROS elevation  dhCer alters the binding of active Rac1 to reconstituted organelle membranes  Active Rac1 is enriched in endolysosomes in ifc-KO neurons for ROS genesis  Rac1-NADPH oxidase elicits ROS, degenerating leukodystrophy-related neuronal cells Dihydroceramide and Neurodegeneration Tzou et al. Summary Disruption of sphingolipid homeostasis has been shown to cause neurological disorders. How specific sphingolipid species modulate the pathogenesis remains unknown. The last step of sphingolipid de novo synthesis is the conversion of dihydroceramide to ceramide catalyzed by dihydroceramide desaturase (human DEGS1; Drosophila Ifc). Loss of ifc leads to dihydroceramide accumulation and oxidative stress, resulting in photoreceptors degeneration, while DEGS1 variants were associated with leukodystrophy and neuropathy. Here, we demonstrated that ifc regulates Rac1 compartmentalization in fly photoreceptors and further showed that dihydroceramide alters the association of active Rac1 to membranes mimicking specific organelles. We also revealed that the major source of ROS originated from Rac1 and NADPH oxidase (NOX) in the cytoplasm, as the NOX inhibitor apocynin ameliorated the oxidative stress and functional defects in both fly ifc-KO photoreceptors and human neuronal cells with diseaseassociated variant DEGS1 H132R . Therefore, DEGS1/ifc deficiency causes dihydroceramide accumulation, resulting in Rac1 translocation and NOXdependent neurodegeneration. Dihydroceramide and Neurodegeneration Tzou et al. Graphical Abstract A DEGS1/ifc converts dihydroceramide to ceramide in neuronal cells, and the endolysosomal NOX complex is not activated. B Dihydroceramide accumulates without functional DEGS1/ifc and causes alterations in membrane microdomains and recruits active Rac1 to endolysosomes. The activation of endolysosomal Rac1-NOX complex elevates cytosolic ROS levels, causing neurodegeneration. Dihydroceramide and Neurodegeneration Tzou et al. In Brief (eTOC blurb) Deficiency in dihydroceramide desaturase causes oxidative stress-mediated neurological disorders. Tzou and Su et al. show that increased dihydroceramide causes the relocalization of active Rac1, whilst inhibition of the Rac1-NOX ameliorates the oxidative stress and neuronal defects. NOX inhibitor apocynin may provide new direction of treatments for patients with DEGS1 variants. Keywords: DEGS1/dihydroceramide/neurodegeneration/oxidative stress/Rac1 signaling Dihydroceramide and Neurodegeneration Tzou et al.

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Ceramide Induces the Death of Retina Photoreceptors Through Activation of Parthanatos

Cited by 34 publications

References 84 publications

Sphingolipids as critical players in retinal physiology and pathology

Sphingolipids as critical players in retinal physiology and pathology

Mithramycin selectively attenuates DNA-damage-induced neuronal cell death

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

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