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Digestion of the glycosaminoglycan extracellular matrix by chondroitinase ABC supports retinal ganglion cell dendritic preservation in a rodent model of experimental glaucoma.

ABSTRACT: Retinal ganglion cell dendritic atrophy is an early feature of glaucoma, and the recovery of retinal ganglion cell dendrites is a viable option for vision improvement in glaucoma. Retinal ganglion cell neurites are surrounded by a specialised glycosaminoglycan extracellular matrix which inhibits dendritic plasticity. Since digestion of the extracellular matrix by chondroitinase ABC has been reported to have neuro-regenerative and neuro-plastic effects within the central nervous system, we explored its potential for dendritic recovery in a rat model of ocular hypertension. Chondroitinase ABC was administrated intravitreally 1?week after ocular hypertension (a time point where dendritic atrophy has already occurred). Retinal ganglion cell dendritic morphology was unaffected by chondroitinase ABC in normal retina. In ocular hypertensive eyes retinal ganglion cells showed significantly decreased dendritic length and area under the Sholl curve with atrophy confined to higher order dendrites. These changes were not observed in chondroitinase ABC injected eyes despite similar total retinal ganglion cell loss (i.e. dendritic protection of surviving retinal ganglion cells). These data suggest that glycosaminoglycan digestion could have a therapeutic role in mitigating the effects of elevated pressure on retinal ganglion cell dendritic structure in glaucoma.

SUBMITTER: Tribble JR

PROVIDER: S-EPMC6249825 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Digestion of the glycosaminoglycan extracellular matrix by chondroitinase ABC supports retinal ganglion cell dendritic preservation in a rodent model of experimental glaucoma.

Tribble James R JR Williams Pete A PA Caterson Bruce B Sengpiel Frank F Morgan James E JE

Molecular brain 20181121 1

Retinal ganglion cell dendritic atrophy is an early feature of glaucoma, and the recovery of retinal ganglion cell dendrites is a viable option for vision improvement in glaucoma. Retinal ganglion cell neurites are surrounded by a specialised glycosaminoglycan extracellular matrix which inhibits dendritic plasticity. Since digestion of the extracellular matrix by chondroitinase ABC has been reported to have neuro-regenerative and neuro-plastic effects within the central nervous system, we explor ...[more]

PMID: 30463575

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Project description:The BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models of neurodegeneration, including glaucomatous optic neuropathy (glaucoma), which degrades the retinal ganglion cell (RGC) axonal projection to the visual brain. Glaucoma is commonly associated with increased sensitivity to intraocular pressure (IOP) and involves a proximal program that leads to RGC dendritic pruning and a distal program that underlies axonopathy in the optic projection. While genetic deletion of the Bcl2-associated X protein (Bax-/-) prolongs RGC body survival in models of glaucoma and optic nerve trauma, axonopathy persists, thus raising the question of whether dendrites and the RGC light response are protected. Here, we used an inducible model of glaucoma in Bax-/- mice to determine if Bax contributes to RGC dendritic degeneration. We performed whole-cell recordings and dye filling in RGCs signaling light onset (αON-Sustained) and offset (αOFF-Sustained). We recovered RGC dendritic morphologies by confocal microscopy and analyzed dendritic arbor complexity and size. Additionally, we assessed RGC axon function by measuring anterograde axon transport of cholera toxin subunit B to the superior colliculus and behavioral spatial frequency threshold (i.e., spatial acuity). We found 1 month of IOP elevation did not cause significant RGC death in either WT or Bax-/- retinas. However, IOP elevation reduced dendritic arbor complexity of WT αON-Sustained and αOFF-Sustained RGCs. In the absence of Bax, αON- and αOFF-Sustained RGC dendritic arbors remained intact following IOP elevation. In addition to dendrites, neuroprotection by Bax-/- generalized to αON-and αOFF-Sustained RGC light- and current-evoked responses. Both anterograde axon transport and spatial acuity declined during IOP elevation in WT and Bax-/- mice. Collectively, our results indicate Bax contributes to RGC dendritic degeneration and distinguishes the proximal and distal neurodegenerative programs involved during the progression of glaucoma.

Project description:BackgroundThere is currently no effective treatment for promoting regeneration of injured nerves in patients who have sustained injury to the central nervous system such as spinal cord injury. Chondroitinase ABC is an enzyme, which promotes neurite outgrowth and regeneration. It has shown considerable promise as a therapy for these conditions. The aim of the study is to determine if targeting chondroitinase ABC expression to the neuronal axon can further enhance its ability to promote axon outgrowth. Long-distance axon regeneration has not yet been achieved, and would be a significant step in attaining functional recovery following spinal cord injury.Methodology/principal findingsTo investigate this, neuronal cultures were transfected with constructs encoding axon-targeted chondroitinase, non-targeted chondroitinase or GFP, and the effects on neuron outgrowth and sprouting determined on substrates either permissive or inhibitory to neuron regeneration. The mechanisms underlying the observed effects were also explored. Targeting chondroitinase to the neuronal axon markedly enhances its ability to promote neurite outgrowth. The increase in neurite length is associated with an upregulation of β-integrin staining at the axonal cell surface. Staining for phosphofocal adhesion kinase, is also increased, indicating that the β-integrins are in an activated state. Expression of chondroitinase within the neurons also resulted in a decrease in expression of PTEN and RhoA, molecules which present a block to neurite outgrowth, thus identifying two of the pathways by which ChABC promotes neurite outgrowth.Conclusions / significanceThe novel finding that targeting ChABC to the axon significantly enhances its ability to promote neurite extension, suggests that this may be an effective way of promoting long-distance axon regeneration following spinal cord injury. It could also potentially improve its efficacy in the treatment of other pathologies, where it has been shown to promote recovery, such as myocardial infarction, stroke and Parkinson's disease.

Dataset Information

Digestion of the glycosaminoglycan extracellular matrix by chondroitinase ABC supports retinal ganglion cell dendritic preservation in a rodent model of experimental glaucoma.

Publications

Digestion of the glycosaminoglycan extracellular matrix by chondroitinase ABC supports retinal ganglion cell dendritic preservation in a rodent model of experimental glaucoma.

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