Early alterations of RNA binding protein (RBP) homeostasis and ER stress-mediated autophagy triggers progressive retinal degeneration in the rd10 mouse model of retinitis pigmentosa (RP)

Abstract The retinal degeneration 10 (rd10) mouse model is widely used to study retinitis pigmentosa (RP) pathomechanisms. It offers a rather unique opportunity to study trans-neuronal degeneration because the cell populations in question are separated anatomically and the mutated Pde6b gene is selectively expressed in rod photoreceptors. We hypothesized that RNA binding protein (RBP) aggregation and abnormal autophagy might serve as early pathogenic events, damaging non-photoreceptor retinal cell types that are not primarily targeted by the Pde6b gene defect. Therefore, we specifically aimed to detect silent, yet dynamic, early molecular pathologies which trigger the sequence of neurodegenerative events in the rd10 retina. We found that early, robust increases in levels of the protective endoplasmic reticulum (ER) Ca2+ buffering chaperone Sigma receptor 1 (SigR1) together with other ER-Ca2+ buffering proteins including calreticulin and protein disulfide isomerase (PDI) indicative of Ca2+-induced ER stress were evident in both photoreceptors and non-photoreceptor neuronal cells before any morphologically noticeable photoreceptor degeneration. In line with this, we found markedly altered expression of autophagy proteins, especially, p62 and LC3 together with abnormal ER widening and large autophagic vacuoles as detected by EM. Interestingly, these changes were accompanied by early, prominent cytoplasmic and nuclear aggregation of the key RBPs pTDP-43 of the FET family RBPs FUS, EWRS1, and TAF15. Co-immunolabelling studies with the stress granule (SG) marker Tia1 revealed that RBP aggregation at least in part proceeded through the SG pathway. The fact that cytoplasmic RBP aggregation occurs in non-photoreceptor retinal neuronal cells before the demise of photoreceptors suggests that functional alterations of connectivity may be sufficient to trigger cytoplasmic RBP mislocalization. These findings in rd10 mice might benefit our understanding of the spread of pathology in many age-related progressive neurodegenerative diseases that are characterized by Ca2+ imbalance, autophagy dysregulation, and altered RBP homeostasis.