Abstract
In some diseases the TrkC.T1 isoform is upregulated in glia, associated with glial TNF-α production and neuronal death. What remains unknown are the activating signals in glia, and how paracrine signals may be selective for a targeted neuron while sparing other proximate neurons. We studied these questions in the retina, where Müller glia contacts photoreceptors on one side and retinal ganglion cells on the other. In a mutant Rhodopsin mouse model of retinitis pigmentosa (RP) causing progressive photoreceptor death—but sparing retinal ganglion cells—TrkC.T1 and NT-3 ligand are upregulated in Müller glia. TrkC.T1 activity generates p-Erk, which causes increased TNF-α. These sequential events take place predominantly in Müller fibers contacting stressed photoreceptors, and culminate in selective death. Each event and photoreceptor death can be prevented by reduction of TrkC.T1 expression, by pharmacological antagonism of TrkC or by pharmacological inhibition Erk. Unmasking the sequence of non-cell autologous events and mechanisms causing selective neuronal death may help rationalize therapies.
Highlights
Retinitis pigmentosa (RP) is an inherited degenerative retinal disease characterized by progressive apoptosis of photoreceptors that leads to irreversible loss of vision[1]
Note that the thinning of the retina is delayed in RHOP:T1 retinas compared with RHOP, n = 8–10 mice per group, ***p < 0.001 (RHOP versus WT) and *p < 0.05 (RHOP versus RHOP:T1). b Fourierdomain optical coherence tomography (FD-optimum cutting temperature (OCT)) representative retina images from WT, RHOP and RHOP:T1 mice at PN days 20 and 24, scale bar = 30 μm. c Quantification of the number of photoreceptors per mm[2] in ultrathin retinal sections
The decrease in retinal p-Akt may be due to TrkC-FL inhibition by KB1368, because KB1368 can antagonize both TrkC.T1 and TrkC-FL37 and p-Akt is downstream of TrkC-FL. These results indicate that in retinitis pigmentosa (RP) Müller cells upregulate TrkC.T1 and NT-3 and that genetic ablation or pharmacological inhibition of TrkC.T1 reduces p-Erk and tumor necrosis factor-α (TNF-α) that are otherwise increased in Müller cells
Summary
Retinitis pigmentosa (RP) is an inherited degenerative retinal disease characterized by progressive apoptosis of photoreceptors that leads to irreversible loss of vision[1]. Photoreceptor death can be triggered by one of more than 250 gene mutations[2,3,4]. There are no effective treatments that can halt or reverse the disease due to the extremely heterogeneous nature of the mutations and the poor understanding of molecular mechanisms that cause photoreceptor cell death. We investigate a disease mechanism that could yield a disease-modifying target. Inflammatory events such as expression of glial tumor necrosis factor-α (TNF-α) are clearly involved in photoreceptor degeneration[5, 6]. The mechanisms that activate retinal TNF-α production in disease remain unclear, and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2)[7,8].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
