Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa

Abstract

Synaptic loss, neuronal death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa (RP), the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. We present evidence linking impaired insulin receptor signaling with RP. We describe a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell axons in the rd10 mouse model of RP, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function in electroretinogram and optomotor tests. These findings support the therapeutic potential of proinsulin in RP.

Tlr2 Gene Deletion Delays Retinal Degeneration in Two Genetically Distinct Mouse Models of Retinitis Pigmentosa

“…Our findings underscore the importance and feasibility of targeting common pathways as a therapeutic strategy for the global treatment of the multiple varieties of RP caused by distinct mutations. We previously demonstrated that multi-faceted neuroprotective drugs can provide structural and functional benefits in several RP animal models [ 48 , 49 , 50 , 51 ]. Here, we show that the targeting of Tlr2 has a disease-modifying effect in RP, regardless of the causative mutation; thus validating TLR2 as a potential therapeutic target for RP treatment.…”