Different contributions of autophagy to retinal ganglion cell death in the diabetic and glaucomatous retinas

Park, Hae-Young Lopilly; Kim, Joo Hang

doi:10.1038/s41598-018-30165-7

Cited by 49 publications

(42 citation statements)

References 36 publications

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“…This may be due in part to the composition of the optic nerve itself, which is mostly glia (41). Within retinal ganglion cells, pAMPK additionally appears to be localized somatically rather than within the axon in glaucoma models (55). Furthermore, in a chronic mouse model of glaucoma, AMPK within the optic nerve is primarily localized and phosphorylated within astrocytes rather than axons (18).…”

Section: Discussionmentioning

confidence: 99%

Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress

Cooper

Pasini

Lambert

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled neurodegeneration in glaucoma, the world’s leading cause of irreversible blindness, and measured how metabolites mobilize through astrocyte gap junctions composed of connexin 43 (Cx43). We elevated intraocular pressure in one eye and determined how astrocyte-derived metabolites in the contralateral optic projection responded. Remarkably, astrocyte networks expand and redistribute metabolites along distances even 10 mm in length, donating resources from the unstressed to the stressed projection in response to intraocular pressure elevation. While resource donation improves axon function and visual acuity in the directly stressed region, it renders the donating tissue susceptible to bioenergetic, structural, and physiological degradation. Intriguingly, when both projections are stressed in a WT animal, axon function and visual acuity equilibrate between the two projections even when each projection is stressed for a different length of time. This equilibration does not occur when Cx43 is not present. Thus, Cx43-mediated astrocyte metabolic networks serve as an endogenous mechanism used to mitigate bioenergetic stress and distribute the impact of neurodegenerative disease processes. Redistribution ultimately renders the donating optic nerve vulnerable to further metabolic stress, which could explain why local neurodegeneration does not remain confined, but eventually impacts healthy regions of the brain more broadly.

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Section: Discussionmentioning

confidence: 99%

Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress

Cooper

Pasini

Lambert

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, the increase of autophagy in early stages of a disease or a punctual damaging input protects retinal cells, but sustained or dysfunctional autophagy may result harmful, particularly to photoreceptor and retinal ganglion cells. Indeed, dysfunctional autophagy, and particularly mitophagy, have been associated to diabetic retinopathy and glaucoma [61].…”

Section: Cross-talk Between Autophagy and The Endoplasmic Reticulum (mentioning

confidence: 99%

“…These free radicals are generated from glucose auto-oxidation reactions and glycated adducts of proteins. These metabolic changes increase the levels of pro-inflammatory cytokines, chemokines and other mediators of the inflammatory response stimulating an influx of leucocytes and altering vascular permeability, which altogether favors the degeneration of the retina [21,26,61,94].…”

Section: Oxidative Stress and Diabetic Retinopathy (Dr)mentioning

confidence: 99%

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

2020

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Retinal cell survival requires an equilibrium between oxygen, reactive oxygen species, and antioxidant molecules that counteract oxidative stress damage. Oxidative stress alters cell homeostasis and elicits a protective cell response, which is most relevant in photoreceptors and retinal ganglion cells, neurons with a high metabolic rate that are continuously subject to light/oxidative stress insults. We analyze how the alteration of cellular endogenous pathways for protection against oxidative stress leads to retinal dysfunction in prevalent (age-related macular degeneration, glaucoma) as well as in rare genetic visual disorders (Retinitis pigmentosa, Leber hereditary optic neuropathy). We also highlight some of the key molecular actors and discuss potential therapies using antioxidants agents, modulators of gene expression and inducers of cytoprotective signaling pathways to treat damaging oxidative stress effects and ameliorate severe phenotypic symptoms in multifactorial and rare retinal dystrophies.

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“…High intraocular pressure (IOP) is considered as the most important risk factor for glaucoma 6 . Although numerous autophagosomes have been found in retinas, and the autophagy-related genes LC3 and Beclin1 are upregulated in experimental models of glaucoma 4,5,7 , the role of autophagy in glaucomatous RGC injury is still controversial. In a rat model of chronic ocular hypertension (COH), inhibition of autophagy reduced RGC apoptosis 8 .…”

Section: Introductionmentioning

confidence: 99%

Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension

et al. 2020

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Autophagy has a fundamental role in maintaining cell homeostasis. Although autophagy has been implicated in glaucomatous pathology, how it regulates retinal ganglion cell (RGC) injury is largely unknown. In the present work, we found that biphasic autophagy in RGCs occurred in a mouse model of chronic ocular hypertension (COH), accompanied by activation of Rac1, a member of the Rho family. Rac1 conditional knockout (Rac1 cKO) in RGCs attenuated RGC apoptosis, in addition to blocking the increase in the number of autophagosomes and the expression of autophagy-related proteins (Beclin1, LC3-II/I, and p62) in COH retinas. Electron micrograph and double immunostaining of LAMP1 and LC3B showed that Rac1 cKO accelerated autolysosome fusion in RGC axons of COH mice. Inhibiting the first autophagic peak with 3-methyladenine or Atg13 siRNA reduced RGC apoptosis, whereas inhibiting the second autophagic peak with 3-MA or blocking autophagic flux by chloroquine increased RGC apoptosis. Furthermore, Rac1 cKO reduced the number of autophagosomes and apoptotic RGCs induced by rapamycin injected intravitreally, which suggests that Rac1 negatively regulates mTOR activity. Moreover, Rac1 deletion decreased Bak expression and did not interfere with the interaction of Beclin1 and Bcl-2 or Bak in COH retinas. In conclusion, autophagy promotes RGC apoptosis in the early stages of glaucoma and results in autophagic cell death in later stages. Rac1 deletion alleviates RGC damage by regulating the cross talk between autophagy and apoptosis through mTOR/Beclin1-Bak. Interfering with the Rac1/mTOR signaling pathway may provide a new strategy for treating glaucoma.

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Different contributions of autophagy to retinal ganglion cell death in the diabetic and glaucomatous retinas

Cited by 49 publications

References 36 publications

Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress

Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension

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