Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa
Sánchez-Cruz, Alonso (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Hernández-Pinto, Alberto (Centro de Investigaciones Biológicas Margarita Salas (CSIC))
Lillo, Concepción (Universidad Salamanca)
Isiegas, Carolina (Centro de Investigaciones Biológicas Margarita Salas (CSIC))
Marchena, Miguel (Centro de Investigaciones Biológicas Margarita Salas (CSIC))
Lizasoain, Ignacio (Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12))
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
de la Villa, Pedro (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Hernández-Sánchez, Catalina (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas)
de la Rosa, Enrique J. (Centro de Investigaciones Biológicas Margarita Salas (CSIC))

Date:	2022
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 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.
Grants:	Instituto de Salud Carlos III PI20/00535 Instituto de Salud Carlos III PI18/01536 Ministerio de Economía y Competitividad RD16/0019/0009
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Neurodegeneration ; Diseases
Published in:	Cell death and disease, Vol. 13 (april 2022) , ISSN 2041-4889

DOI: 10.1038/s41419-022-04839-0
PMID: 35444190

14 p, 6.2 MB

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