Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa

Sánchez-Cruz, Alonso; Villarejo‐Zori, Beatriz; Marchena, Miguel; Zaldívar-Díez, Josefa; Palomo, Valle; Gil, Carmen; Lizasoaín, Ignacio; Villa, Pedro de la; Martı́nez, Ana; Rosa, Enrique J. de la; Hernández‐Sánchez, Catalina

doi:10.1186/s13024-018-0251-y

Cited by 33 publications

(30 citation statements)

References 31 publications

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“…inhibitors (Figure 4.3). Remarkably, these in vitro findings have been corroborated in vivo in rd10 mice, in which loss visual function is attenuated by inhibiting GSK-3 50 . Taken together with other published data, these findings support the clinical therapeutic potential of GSK-3 inhibitors for the treatment of retinal dystrophies.…”

Section: Conditions Of the Brain And Retinamentioning

confidence: 65%

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CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

Rosa¹,

Hernández‐Sánchez²

2018

Drug Discovery

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As an extension of the central nervous system (CNS), the retina shares with the brain certain developmental, physiological, and pathological characteristics. However, the underlying mechanisms and pathological signs common to neurodegenerative conditions of both the retina and brain have been relatively overlooked. In animal models and in human patients, marked retinal alterations have been demonstrated in Alzheimer´s disease, Parkinson´s disease, and multiple sclerosis, among other pathologies. Furthermore, neurodegeneration of the retina and brain appears to be mediated by similar mechanisms, which include protein aggregation, neuroinflammation, and cell death. Analysis of the retina, which is easily accessible to objective techniques, may therefore constitute an effective tool for the screening and follow-up of CNS neurodegeneration. Moreover, patients with retinal neurodegeneration could potentially benefit from the broad array of pharmacological compounds that have been designed and tested for the treatment of the aforementioned CNS pathologies. Supporting this view, we have shown that GSK-3 inhibitors, which have already been tested in clinical trials to treat several neurodegenerative conditions of the brain, attenuate retinal damage and vision loss in a mouse model of retinitis pigmentosa. Furthermore, systemic proinsulin treatment preserves visual and cognitive function in mouse models of retinitis pigmentosa and precocious aging, respectively.

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Section: Conditions Of the Brain And Retinamentioning

confidence: 65%

“…D) In vivo treatment with VP3.15 partially preserves visual function, as determined by electroretinography (amplitudes of two relevant waves at P32 are shown). Experimental data taken from50 .…”

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confidence: 99%

CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

Rosa¹,

Hernández‐Sánchez²

2018

Drug Discovery

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“…Moreover, the widespread expression of INSR in the retina suggests that synaptic maintenance promoted by INSR signaling is only one of several retinal processes regulated by INSR. Indeed, we and others have demonstrated the neuroprotective effects of INSR signaling molecules on photoreceptor survival [57][58][59].…”

Section: Discussionmentioning

confidence: 79%

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

Sánchez-Cruz

Hernández‐Pinto

Lillo

et al. 2020

Preprint

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Background Synaptic loss, neuronal cell death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa, the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor cell 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. Methods We employed a gene therapy strategy to enhance insulin receptor signaling in the Pde6b rd10/rd10 mouse model of RP by using recombinant AAV serotype 2/1 viral vectors bearing cDNA from the human proinsulin gene. Insulin receptor expression and signaling were analyzed by PCR and immunostaining. Synaptic connectivity was evaluated by electron microscopy and immunostaining. Proinsulin levels were measured by ELISA. Photoreceptor preservation was assayed by histological analysis and visual function was assessed by electroretinography and optomotor test. Results We present evidence linking impaired insulin receptor signaling with retinitis pigmentosa. We found 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 retinitis pigmentosa, 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 as determined by electroretinography and optomotor tests. Conclusion These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa.

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Section: Aav-hpi Treatment In Rd10 Mice Preserves Visual Functionmentioning

confidence: 79%

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

Cruz

Pinto

Lillo

et al. 2020

Preprint

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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.

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Modulation of GSK-3 provides cellular and functional neuroprotection in the rd10 mouse model of retinitis pigmentosa

Cited by 33 publications

References 31 publications

CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

CHAPTER 4. CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

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

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

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