Sequences of Alterations in Inflammation and Autophagy Processes in Rd1 Mice

Simple Summary In this work, we have demonstrated alterations in microglia and macroautophagy in rd1 mice (one retinitis pigmentosa (RP) model) at the first stages of the disease (when the rods are dying). When there are almost no rods, and the cones are dying, chaperone-mediated autophagy alterations (CMA) are found in RP retinas. Based on our results, it would be reasonable to conclude that inflammation and macroautophagy processes could be possible alternatives in the treatment of RP, in the initial stages. In this phase, cones, which are mainly responsible for human vision, have not yet degenerated, thus allowing a very high quality of life for patients if retinal degeneration can be stopped or slowed down in this phase. On the other hand, CMA would constitute a possible therapeutic target later, when cones are degenerating.Abstract (1) Background: the aim of this work was to study microglia and autophagy alterations in a one retinitis pigmentosa (RP) model at different stages of the disease (when rods are dying and later, when there are almost no rods, and cones are the cells that die. (2) Methods: rd1 mice were used and retinas obtained at postnatal days (PN) 11, 17, 28, 35, and 42. Iba1 (ionized calcium-binding adapter molecule 1) was the protein selected to study microglial changes. The macroautophagy markers Beclin-1, Atg5, Atg7, microtubule-associated protein light chain 3 (LC3), and lysosomal-associated membrane protein 2 (LAMP2) (involved in chaperone-mediated autophagy (CMA)) were determined. (3) Results: the expression of Iba1 was increased in rd1 retinas compared to the control group at PN17 (after the period of maximum rod death), PN28 (at the beginning of the period of cone death), and PN42. The number of activated (ameboid) microglial cells increased in the early ages of the retinal degeneration and the deactivated forms (branched cells) in more advanced ages. The macroautophagy markers Atg5 at PN11, Atg7 and LC3II at PN17, and Atg7 again at PN28 were decreased in rd1 retinas. At PN35 and PN42, the results reveal alterations in LAMP2A, a marker of CMA in the retina of rd1 mice. (4) Conclusions: we can conclude that during the early phases of retinal degeneration in the rd1 mouse, there is an alteration in microglia and a decrease in the macroautophagy cycle. Subsequently, the CMA is decreased and later on appears activated as a compensatory mechanism.

Automated summary

This study demonstrates alterations in microglia and macroautophagy in an RP mouse model during the early stages of the disease. It suggests that inflammation and macroautophagy processes could be potential treatment alternatives for RP, while chaperone-mediated autophagy could be a therapeutic target in later stages. These findings provide important insights into the pathogenesis of RP and the development of treatment strategies.