The Role Of Vps35in Retinal Ganglion Cell Degeneration

BackgroundRetinal ganglion cells(RGCs) is the only output neuron in the retina, the RGCs axonalaggregates form the optic nerve, which is responsible for transmission of visual informationfrom the eye to the brain. Retinal ganglion cell degeneration is the very importantpathogenic factor of many ocular diseases leading to blindness such as glaucoma anddiabetic retinopathy(DR). Both of the RGCs axons under the stress of some mechanicalfactors such as the elevated intraocular pressure(IOP), and the ischemia or hypoxia causedby some reasons making energy supply shortage of the axonal transport can lead to theblock of RGC axonal transport and injury and degeneration of RGC axons. On the otherhand, the destruction of RGC axonal transport results to the lack of neurotrophic factorstransported along the RGC axons from the brain to the RGC somata, then further to thedegeneration of RGC degeneration. At the same time, the neurotoxic substances producedby the impaired RGCs are released to the surrounding environment, which lead to thesecondary degeneration of adjacent RGCs. This kind of vicious circle results to theapoptosis of RGCs finally. RGCs belong to the central nervous system and the reversal ofRGC degenenration is very hard. So how to prevent the RGC degeneration and death is oneof the most difficult problems faced by ophthalmologists.Vacuolar protein sorting35(Vps35) is the core of Retromer complex and responsiblefor sorting the membrane protein receptors and retrograde transport of them from endosometo Trans-Golgi Network(TGN). This retrograde transport facilitates the recycle of theseprotein receptors, inhibits the degradation of these proteins in lysosomes and protects thebalance of cellular metabolism. Vps35is highly conserved from simple unicellulareukaryote to human, suggesting a relatively early evolutionary appearance and functionalindispensability. Recently many researches verified the defect of Vps35is tightly relatedwith many neurodegenerative diseases such as Alzheimer’s disease(AD) and Parkinson’sdisease(PD). Glaucoma is similar with AD because both of them are central nervous systemdiseases and age-related. Does Vps35express in the retina? And does the defect of Vps35 result in retinal degeneration or not?ObjectivesTo Confirm the expression of Vps35in the retina and the role of Vps35in retinalganglion cell degeneration, further explore the mechanism of Vps35in retinal ganglion celldegeneration.MethodsTo test the hypothesis we applied the retinae of Vps35gene knockout heterozygousmice(Vps35+/m) and their wildtype littermates(Vps35+/+), detected Vps35expression in theretina and observed the retinal ganglion cell degeneration caused by Vps35-loss by theexperimental techniques including X-gal staining, immunofluorescence, western blot,RT-PCR, HE staining, TUNEL and so on.ResultsOur data showed that Vps35expressed in the mouse retinal ganglion cells(RGCs), thedefect of Vps35resulted in reduced axon fibers, dystrophic dendrites, and increasedapoptosis of RGCs, as well as increased hyperphosphorylation of Tau protein in the retinae.ConclusionVPS35is selectively expressed in mouse RGCs, Vps35-deficiency resulted indegenerative-like features in RGCs and hyperphosphorylation of Tau protein is involved inthe mechanism of RGCs degeneration caused by Vps35-loss. Vps35is a potential target forthe therapy of RGC degeneration in many ocular diseases such as glaucoma and diabeticretinopathy.