de la Rosa, E. J. | bioRxiv Science

bioRxiv2020

Dynamics of central remyelination and treatment evolution in a model of Multiple Sclerosis with Optic Coherence Tomography

The need for remyelinating drugs is essential for healing important diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to follow remyelination in vivo, which is of utmost importance to perform good clinical trials. Here, we show how the optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to follow remyelination in vivo in MS patients. Our pioneer study validates the study of myelin/remyelination in the optic nerve using OCT and reflects what is occurring in non accessible CNS structures, like the spinal cord. For this study we used the oral bioavailable small molecule VP3.15, confirming its therapeutical potential as neuroprotective, antinflammatory and remyelinating drug for MS. Altogether, our present results confirm the usefulness of OCT to monitor the effectivity of remyelinating therapies in vivo and underscore the relevance of VP3.15 as potential disease modifying drug for MS therapy.

neuroscience↗

bioRxiv2020

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

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.

neuroscience↗