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

Alonso Sánchez-Cruz, Alberto Hernández-Pinto, Concepción Lillo, Carolina Isiegas, Miguel Marchena, Ignacio Lizasoain, Fátima Bosch, Pedro de la Villa, Catalina Hernández-Sánchez, Enrique J de la Rosa

Research output: Contribution to journalArticleResearchpeer-review


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 terminals 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, the insulin precursor, 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 point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa.

Original languageEnglish
Article number383
Number of pages14
JournalCell Death & Disease
Issue number4
Publication statusPublished - 20 Apr 2022


  • Animals
  • Disease Models, Animal
  • Insulin
  • Mice
  • Mice, Inbred C57BL
  • Proinsulin/pharmacology
  • Receptor, Insulin
  • Retinitis Pigmentosa/pathology
  • Synapses/metabolism

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