On 6 March at 14:00 Natalia Lobanovskaya will defend her doctoral thesis „The role of PSA-NCAM in the survival of retinal ganglion cells“.
Professor of Pharmacology and ToxicologyAleksandr Žarkovski (PhD. (Medical Studies), UT, Institute of Biomedicine and Translational Medicine).
Professor Dan Lindholm (PhD), Department of Biochemistry and Developmental Biology, University of Helsinki, Helsingi, Soome.
Retinal ganglion cells (RGCs) undergo degeneration in many human diseases, such as glaucoma, diabetic retinopathy, optic nerve atrophy, some inherited diseases (dominant optic atrophy, Leber hereditary optic neuropathy). There is no effective treatment for progressive vision loss due to RGC degeneration. Polysialylated neural cell adhesion molecule (PSA-NCAM) is expressed abundantly in the retina in close proximity to the RGCs. PSA is attached to NCAM by two specific polysialyltransferases, II and IV (ST8SiaII, ST8SiaIV). It is thought that PSA-NCAM affects not only adhesive properties between cells, but also plays a role in the intracellular signaling, which influences cell survival, proliferation, differentiation, migration, axon outgrowth and pathfinding, and synaptic plasticity. The functions of PSA-NCAM in the retina in the adult are not clearly understood. One of the putative roles of PSA-NCAM in the retina is in the maintenance of RGC survival.
The aims of this study were to investigate in detail (a) the survival of RGCs in mice deficient for NCAM and ST8SiaII or ST8SiaIV; (b) the protective roles of NCAM/PSA-NCAM during excitotoxic retinal damage induced by kainic acid (KA); (c) the protective roles of PSA-NCAM in the mouse model of diabetic retinopathy (DR).
Our study demonstrates that the viability and survival of RGCs is dependent on the presence of PSA-NCAM expressed by astroglial and Müller cells. Excitotoxic retinal damage or diabetic retinopathy induces a decrease in the levels of PSA-NCAM and thereby promotes RGC degeneration. The reduction of PSA-NCAM levels in these models is mediated by matrix metalloprotease-9 (MMP-9), which induces shedding of the extracellular domain of PSA-NCAM. Our study demonstrates that PSA-NCAM and MMP-9 might be new pharmacological targets to combat retinal degeneration.