Abstract
ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.
Highlights
Retinitis pigmentosa (RP) refers to a group of inherited retinal dystrophies that are clinically similar despite arising from a large set of genetic mutations
Previous findings demonstrate the involvement of the proNGF/ p75NTR system in optic nerve axotomy, diabetic retinopathy and glaucoma, diseases primarily affecting the retinal ganglion cell neurons.[19,20]
We studied whether this mechanism is functional in a disease primarily affecting photoreceptor neurons, by quantifying the expression of p75NTR and proNGF as well as the downstream effectors TNFα and α2M, and the glial activation during the neurodegenerative process associated with RP
Summary
Retinitis pigmentosa (RP) refers to a group of inherited retinal dystrophies that are clinically similar despite arising from a large set of genetic mutations (http://www.sph.uth.tmc.edu/ Retnet/disease.htm) These mutations usually trigger photoreceptor cell degeneration and death, leading to visual function decline and, eventually, blindness.[1] While the time of onset and the rate of neurodegeneration are specified by the mutation, most, if not all, forms of RP share molecular and cellular mechanisms that include inflammation, microglial activation and reactive gliosis. The genetic complexity in the etiology of RP, comprising more than 300 described mutations in over 50 different genes, calls for the development of treatments targeting common mechanisms independently of the causative mutation This would entail the detailed characterization of the processes leading to retinal deterioration, as a strategy to discover novel therapeutic targets. Other proneurotrophins bind p75NTR, their functional impact is less characterized than in the case of proNGF.[18]
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