Towards elucidating the molecular pathology of X-linked juvenile retinoschisis: investigating the interaction of the retinoschisin protein with the Na/K-ATPase

• Applicant: Dr. Ulrike Friedrich
• Subject Area: Human Genetics
• Term: from 2013 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 241648798

X-linked juvenile retinoschisis (XLRS) is a degenerative retinal disease, caused by mutations in the RS1 gene on Xp22.13. RS1 encodes for a protein termed retinoschisin, which is secreted and subsequently binds to the outer cell membrane of photoreceptor and bipolar cells. Its regular function in XLRS pathogenesis is poorly understood. The retinal Na/K-ATPase was identified as a direct interaction partner, anchoring retinoschisin to the plasma membrane. In addition, our recent studies show that retinoschisin acts as a regulator of intracellular signaling and apoptosis. Exactly how retinoschisin exerts these functions is unknown. We speculate, however, that perturbances in the homoeostatic signal processes could be causal in XLRS pathology. Thus, our first aim is to delineate the molecular events responsible for the effect of retinoschisin on intracellular signaling. To this end, we plan to identify direct interaction partners of the retinoschisin-Na/K-ATPase complex as well as subsequent signal transducers, and determine the influence of retinoschisin on these constituents. The second aim of this project is to analyze the interaction of retinoschisin and the cardiac glycoside ouabain in processes such as binding and regulation of the Na/K-ATPase. We also seek to determine the consequences if this interaction on retinal integrity. A third aim is to identify the molecular interfaces of retinoschisin and the Na/K-ATPase allowing the computation of a model of the retinoschisin-Na/K-ATPase complex. Our studies shall result in a deeper understanding of the initial steps in the pathobiology of XLRS. Considering the limited therapeutic options for XLRS-treatment, this could provide innovative starting points for the development of novel and targeted therapeutics.

• DFG Programme: Research Grants