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Editors Selection IGR 22-4

Basic Research: BDNF and Lingo-1 Fusion Protein on long-term survival of RGC

Comment by David Calkins on:

24268 Combined effect of brain-derived neurotrophic factor and LINGO-1 fusion protein on long-term survival of retinal ganglion cells in chronic glaucoma, Fu Q-L; Li X; Yip HK et al., Neuroscience, 2009; 162: 375-382

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Neurotrophic factors and agents have long held interest for their potential to protect retinal ganglion cells and their axons from glaucomatous or other insults. Brain-derived neurotrophic factor (BDNF) in particular has shown some promise for promoting ganglion cell survival in animal models of glaucoma¹, but the long-term effects of administration are equivocal². The action of endogenous BDNF is regulated by numerous cascades, some of which may decrease the availability of BDNF for binding its receptor TrkB. LINGO-1 is Ig-containing protein found in the central nervous system that inhibits axonal myelination and regeneration and negatively regulates other growth factors³. Fu et al. (1230) investigated whether intravitreal injection of both recombinant BDNF and a LINGO-1 fusion protein was protective of ganglion cells in the laser-induced ocular hypertension model. These injections along with control injections were performed weekly for the duration of the four-week experiments. As in many such studies, the sole outcome measure for RGC survival is quantification of retrograde labeling from fluorogold injections into the superior colliculus. Injection of the two compounds together elicited about a 30% increase in labeled cells comparable to levels in the normal-IOP eye. This may not indicate increased survival per se, but rather an enhanced fraction of RGCs with dynein-mediated active axonal transport, which is the basis for fluorogold transport⁴. One would like to see further evidence of a protective signature. Ocular hypertension also appeared to increase co-localized TrkB and LINGO-1 in fluorogold identified ganglion cells. Finally, western blots revealed that the injection combination of BNDF and LINGO-1 fusion protein increased levels of activated TrkB more than BDNF alone. This paralleled the fluorogold results which were less robust for BDNF alone. A key question raised by the study is the precise action of the LINGO-1 fusion protein, which is ambiguous despite references to unpublished data showing surface binding to endogenous LINGO-1. Finally, since the intervention was performed throughout the hypertensive period, whether the protective effects are long-term remains unanswered.

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