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Sequences of Alterations in Inflammation and Autophagy Processes in Rd1 Mice
Javier Martínez-González1, Ángel Fernández-Carbonell1, Antolin Cantó1
1Department of Biomedical Sciences, Faculty of Health Sciences, Institute of Biomedical Sciences, Cardenal Herrera-CEU University, CEU Universities, 46115 Valencia, Spain.
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.
Insights
This study reveals that in retinitis pigmentosa (RP) mouse models, microglia and autophagy pathways are altered during disease progression. Early RP shows decreased macroautophagy, followed by changes in chaperone-mediated autophagy (CMA) as a potential compensatory response.
Area of Science:
- Ophthalmology
- Neuroscience
- Cell Biology
Background:
- Retinitis pigmentosa (RP) is a group of inherited retinal diseases causing progressive vision loss.
- Understanding the cellular mechanisms, including microglial activation and autophagic processes, is crucial for developing therapeutic strategies.
- The rd1 mouse model recapitulates key features of RP, making it valuable for studying disease pathogenesis.
Purpose of the Study:
- To investigate alterations in microglia and autophagy during different stages of retinal degeneration in the rd1 mouse model.
- To analyze the expression of key proteins involved in macroautophagy and chaperone-mediated autophagy (CMA).
- To correlate these molecular changes with the progression of photoreceptor cell death.
Main Methods:
- Retinas from rd1 mice were collected at various postnatal days (PN 11, 17, 28, 35, 42).
- Microglial activation was assessed by quantifying ionized calcium-binding adapter molecule 1 (Iba1) expression and cell morphology.
- Autophagy markers, including Beclin-1, Atg5, Atg7, LC3, and LAMP2 (for CMA), were determined using molecular techniques.
Main Results:
- Increased Iba1 expression and a shift in microglial morphology (ameboid to branched) were observed during disease progression.
- A decrease in macroautophagy markers (Atg5, Atg7, LC3II) was noted in early to mid-stages of degeneration.
- Alterations in LAMP2A, a marker for CMA, were detected in later stages, suggesting a compensatory role.
Conclusions:
- Microglia and macroautophagy are significantly altered during the progression of retinal degeneration in the rd1 mouse model.
- Early stages of RP involve impaired macroautophagy, while later stages show changes in CMA, potentially as a compensatory mechanism.
- These findings highlight the complex interplay of cellular stress responses in RP pathogenesis.
