Experimental treatments for retinitis pigmentosa in animal models: targeting insulin receptor, GSK-3 and Toll-like receptors
| Autor: | Sánchez Cruz, Alonso |
|---|---|
| Přispěvatelé: | Lizasoain Hernández, Ignacio, Hernández Sánchez, Catalina |
| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | E-Prints Complutense. Archivo Institucional de la UCM instname E-Prints Complutense: Archivo Institucional de la UCM Universidad Complutense de Madrid |
| Popis: | Retinitis pigmentosa (RP) is a rare disease responsible for the majority of the cases of hereditary blindness. RP is a genetically heterogeneous disease caused by more than 3000 mutations in over 60 genes without an effective treatment. Irrespectively of the causative mutation, there are common traits to RP: photoreceptor cell death and retinal inflammation. In this thesis we have studied three potential mutation-independent therapeutic strategies for RP treatment. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Here we present evidence linking impaired insulin receptor signaling with RP. In physiological conditions, insulin receptor is expressed in all the retinal layers depicting prominent levels in horizontal and ganglion cells fibers. In the rd10 retinas, a mouse model of RP, the insulin receptor and its downstream effector phospho-S6 were selectively decreased in the horizontal cells. In parallel, we observed aberrant synapses between rod photoreceptors and the post-synaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin production restored retinal insulin receptor signaling, increasing S6 phosphorylation. Moreover, proinsulin preserved photoreceptor cells and synaptic connectivity. These results open a new line of research into interventions aimed at preserving rod connectivity and support the therapeutic potential of proinsulin in RP... |
| Databáze: | OpenAIRE |
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