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Editors Selection IGR 13-2
Basic Science: Neurodegeneration and Neuroprotection
Comment by Francesca Cordeiro on:
65944 Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB, Dekeyster E; Geeraerts E; Buyens T et al., PLoS ONE, 2015; 10: e0142067
One of the most established mechanisms in glaucoma is the induction of retinal ganglion cell (RGC) apoptosis through disruption of retrograde delivery of trophic support - the neurotrophin deprivation hypothesis. However, intraocular and local administration of exogenous neurotrophins to the glaucomatous retina have been met with varying success. The authors speculated that as neuronal response depends where in the pathway signaling is initiated (i.e., in the cell body, in the axon terminals, or on dendrites), delaying or preventing RGC death could be better achieved by interfering with their target areas.
In this new study, Dekeyster et al. test the neurotrophin deprivation hypothesis with an alternative approach. Using rodent models of optic nerve crush and OHT, they assess the induction of retrograde brain-derived neurotrophic factor (BDNF) in the superior colliculus using a viral vector-mediated delivery system. Interestingly, this route was not found to be superior to ocular delivery, with no enhanced display of neuroprotection.
The study was of a high-quality design, with a detailed temporal characterization of RGC degeneration and expression patterns of BDNF and its receptor TrkB in two mouse models of glaucoma. Intracollicular BDNF overexperssion was definitely achieved, yet no real neuroprotective effect was seen.
The authors carefully consider potential underlying causes for this failure, and put forward reduced neurotrophin responsiveness and impaired retrograde transport in response to BDNF overexpression. It should, however, also be considered that viral vector-mediated overexpression of BDNF in the superior colliculus, whilst being a very elegant apporach, may lead to off-target transduction effects involving different superior colliculus layers, cell types, and BDNF isoforms. Nevertheless, this study advances our knowledge about the pivotal role of neurotrophin signalling in the retina and the brain in glaucoma pathogenesis, and draws attention to the complexity of restoring neurotrophic signalling as a future neuroprotective strategy.
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