CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma

Maddineni, Prabhavathi; Kasetti, Ramesh Babu; Patel, Pinkal; Millar, J. A.; Kiehlbauch, Charles C.; Clark, Abbot F.; Zode, Gulab

doi:10.1186/s13024-020-00400-9

Cited by 56 publications

(49 citation statements)

References 66 publications

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“…58 Most of the studies in rodent models with induced ocular hypertension have shown that axonal degeneration and dysfunction precedes RGC death early in course of disease progression, which ultimately leads to the axonal transport obstruction, thereby leading to the RGC loss. [62][63][64][65][66][67][68] In C57BL/6 background mice, the combined null mutation of JNK2 and JNK3 protected dopamine neurons, however, was not able to protect against axon degeneration, after intrastriatal administration of 6hydroxydopamine. 69 On similar grounds, DBA/2J mouse model of ocular hypertension, the knockout of JNK2 and JNK3 protected the somas of RGCs but not the axons from the degeneration.…”

Section: Discussionmentioning

confidence: 99%

Involvement of c-Jun N-terminal kinase 2 (JNK2) in Endothelin-1 (ET-1) Mediated Neurodegeneration of Retinal Ganglion Cells

Kodati

Stankowska

Krishnamoorthy

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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The goal of this study was to determine whether JNK2 played a causative role in endothelin-mediated loss of RGCs in mice.METHODS. JNK2 −/− and wild type (C57BL/6) mice were intravitreally injected in one eye with 1 nmole of ET-1, whereas the contralateral eye was injected with the vehicle. At two time points (two hours and 24 hours) after the intravitreal injections, mice were euthanized, and phosphorylated c-Jun was assessed in retinal sections. In a separate set of experiments, JNK2 −/− and wild type mice were intravitreally injected with either 1 nmole of ET-1 or its vehicle and euthanized seven days after injection. Retinal flat mounts were stained with antibodies to the RGC marker, Brn3a, and surviving RGCs were quantified. Axonal degeneration was assessed in paraphenylenediamine stained optic nerve sections. RESULTS.Intravitreal ET-1 administration produced a significant increase in immunostaining for phospho c-Jun in wild type mice, which was appreciably lower in the JNK2 −/− mice. A significant (P < 0.05) 26% loss of RGCs was found in wild type mice, seven days after injection with ET-1. JNK2 −/− mice showed a significant protection from RGC loss following ET-1 administration, compared to wild type mice injected with ET-1. A significant decrease in axonal counts and an increase in the collapsed axons was found in ET-1 injected wild type mice eyes.

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Section: Discussionmentioning

confidence: 99%

Involvement of c-Jun N-terminal kinase 2 (JNK2) in Endothelin-1 (ET-1) Mediated Neurodegeneration of Retinal Ganglion Cells

Kodati

Stankowska

Krishnamoorthy

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…For immunostaining of paraffin-embedded tissues, 5 μm paraffin sections were prepared, deparaffinized, and subjected to antigen retrieval in citrate buffer (pH 6). Slides were then blocked in 10% goat serum containing 0.1% Triton X-100 for 2 hours and incubated with primary and secondary antibodies as described above and previously ( 69 , 70 ). For immunostaining of TM cells, cells were fixed in 4% PFA for 15 minutes, permeabilized with 0.1% Triton X-100 in PBS for 10 minutes, and stained with the appropriate antibodies as described above.…”

Section: Methodsmentioning

confidence: 99%

Autophagy stimulation reduces ocular hypertension in a murine glaucoma model via autophagic degradation of mutant myocilin

et al. 2021

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Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) damage is associated with Primary Open Angle Glaucoma (POAG). Myocilin mutations resulting in elevated IOP are the most common genetic cause of POAG. We have previously shown that mutant myocilin accumulates in the endoplasmic reticulum (ER) and induces chronic ER stress, leading to TM damage and IOP elevation. However, it is not understood how chronic ER stress leads to TM dysfunction and loss. Here, we report that mutant myocilin activates autophagy but it is functionally impairecd in cultured human trabecular meshwork (TM) cells and in a mouse model of myocilin-associated POAG (Tg-MYOC Y437H). Genetic and pharmacological inhibition of autophagy worsens mutant myocilin accumulation and exacerbates IOP elevation in Tg-MYOC Y437H mice. Remarkably, impaired autophagy is associated with chronic ER stress-induced transcriptional factor, CHOP. Deletion of CHOP corrects impaired autophagy, enhances recognition and degradation of mutant myocilin by autophagy,and reduces glaucoma in Tg-MYOC Y437H mice. Stimulating autophagic flux via Tat-beclin 1 peptide or torin 2, promotes autophagic degradation of mutant myocilin and reduces elevated IOP in Tg-MYOC Y437H mice. Together, our studies provide an alternate treatment strategy for myocilin-associated POAG by correcting impaired autophagy in the TM.

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“…AH Outflow Facility Measurement. AH outflow facility (C) was measured in live anesthetized mice using constant-flow infusion method in a masked manner as described previously (27,(60)(61)(62) and in SI Appendix.…”

Section: Methodsmentioning

confidence: 99%

Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma

Patel

Chen

Kasetti

et al. 2021

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

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Primary Open Angle Glaucoma (POAG) is the most common form of glaucoma that leads to irreversible vision loss. Dysfunction of trabecular meshwork (TM) tissue, a major regulator of aqueous humor (AH) outflow resistance, is associated with intraocular pressure (IOP) elevation in POAG. However, the underlying pathological mechanisms of TM dysfunction in POAG remain elusive. In this regard, transient receptor potential vanilloid 4 (TRPV4) cation channels are known to be important Ca2+ entry pathways in multiple cell types. Here, we provide direct evidence supporting Ca2+ entry through TRPV4 channels in human TM cells and show that TRPV4 channels in TM cells can be activated by increased fluid flow/shear stress. TM-specific TRPV4 channel knockout in mice elevated IOP, supporting a crucial role for TRPV4 channels in IOP regulation. Pharmacological activation of TRPV4 channels in mouse eyes also improved AH outflow facility and lowered IOP. Importantly, TRPV4 channels activated endothelial nitric oxide synthase (eNOS) in TM cells, and loss of eNOS abrogated TRPV4-induced lowering of IOP. Remarkably, TRPV4-eNOS signaling was significantly more pronounced in TM cells compared to Schlemm’s canal cells. Furthermore, glaucomatous human TM cells show impaired activity of TRPV4 channels and disrupted TRPV4-eNOS signaling. Flow/shear stress activation of TRPV4 channels and subsequent NO release were also impaired in glaucomatous primary human TM cells. Together, our studies demonstrate a central role for TRPV4-eNOS signaling in IOP regulation. Our results also provide evidence that impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in glaucoma.

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CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma

Cited by 56 publications

References 66 publications

Involvement of c-Jun N-terminal kinase 2 (JNK2) in Endothelin-1 (ET-1) Mediated Neurodegeneration of Retinal Ganglion Cells

Involvement of c-Jun N-terminal kinase 2 (JNK2) in Endothelin-1 (ET-1) Mediated Neurodegeneration of Retinal Ganglion Cells

Autophagy stimulation reduces ocular hypertension in a murine glaucoma model via autophagic degradation of mutant myocilin

Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma

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