Autophagy in the retinal pigment epithelium: a new vision and future challenges

Intartaglia, Daniela; Giamundo, Giuliana; Conte, Iván

doi:10.1111/febs.16018

Cited by 36 publications

(35 citation statements)

References 128 publications

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“…In the recent years, a specialised form of non‐canonical autophagy namely LC3‐associated phagocytosis (LAP), has been described as a key mechanism in RPE cells for degradation of POSs. It could thus be envisaged that the upregulation of LC3 expression in RP11‐RPE cells could reflect activation of LAP 77 . Although many proteins are common between these two autophagy branches, two key proteins (Rubicon and Nox2), distinguish LAP from canonical autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…It could thus be envisaged that the upregulation of LC3 expression in RP11-RPE cells could reflect activation of LAP. 77 Although many proteins are common between these two autophagy branches, two key proteins (Rubicon and Nox2), distinguish LAP from canonical autophagy. A careful examination of our proteomics data did not reveal any changes in expression of these two proteins in RP11-RPE cells.…”

Section: Discussionmentioning

confidence: 99%

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Activation of autophagy reverses progressive and deleterious protein aggregation in PRPF31 patient‐induced pluripotent stem cell‐derived retinal pigment epithelium cells

Γεωργίου

Yang

Atkinson

et al. 2022

Clinical & Translational Med

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Introduction Mutations in pre‐mRNA processing factor 31 (PRPF31), a core protein of the spliceosomal tri‐snRNP complex, cause autosomal‐dominant retinitis pigmentosa (adRP). It has remained an enigma why mutations in ubiquitously expressed tri‐snRNP proteins result in retina‐specific disorders, and so far, the underlying mechanism of splicing factors‐related RP is poorly understood. Methods We used the induced pluripotent stem cell (iPSC) technology to generate retinal organoids and RPE models from four patients with severe and very severe PRPF31‐adRP, unaffected individuals and a CRISPR/Cas9 isogenic control. Results To fully assess the impacts of PRPF31 mutations, quantitative proteomics analyses of retinal organoids and RPE cells were carried out showing RNA splicing, autophagy and lysosome, unfolded protein response (UPR) and visual cycle‐related pathways to be significantly affected. Strikingly, the patient‐derived RPE and retinal cells were characterised by the presence of large amounts of cytoplasmic aggregates containing the mutant PRPF31 and misfolded, ubiquitin‐conjugated proteins including key visual cycle and other RP‐linked tri‐snRNP proteins, which accumulated progressively with time. The mutant PRPF31 variant was not incorporated into splicing complexes, but reduction of PRPF31 wild‐type levels led to tri‐snRNP assembly defects in Cajal bodies of PRPF31 patient retinal cells, altered morphology of nuclear speckles and reduced formation of active spliceosomes giving rise to global splicing dysregulation. Moreover, the impaired waste disposal mechanisms further exacerbated aggregate formation, and targeting these by activating the autophagy pathway using Rapamycin reduced cytoplasmic aggregates, leading to improved cell survival. Conclusions Our data demonstrate that it is the progressive aggregate accumulation that overburdens the waste disposal machinery rather than direct PRPF31‐initiated mis‐splicing, and thus relieving the RPE cells from insoluble cytoplasmic aggregates presents a novel therapeutic strategy that can be combined with gene therapy studies to fully restore RPE and retinal cell function in PRPF31‐adRP patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of autophagy reverses progressive and deleterious protein aggregation in PRPF31 patient‐induced pluripotent stem cell‐derived retinal pigment epithelium cells

Γεωργίου

Yang

Atkinson

et al. 2022

Clinical & Translational Med

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“…The accumulation of substances to be degraded in the cells and the load placed on them caused degradation by autophagy to become insufficient, resulting in the decrease in phagocytosis. Moreover, autophagy failure is known to occur with aging [51]. Therefore, it is possible that the decrease in phagocytosis was caused by the dysfunction of the degradation process in the RPE, and further investigation is needed to understand the mechanism.…”

Section: Discussionmentioning

confidence: 99%

Lipid Droplet Accumulation Promotes RPE Dysfunction

Yako

Otsu

Nakamura

et al. 2022

IJMS

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Non-exudative age-related macular degeneration (AMD) is an irreversibly progressive retinal degenerative disease characterized by dysfunction and loss of retinal pigment epithelium (RPE). It has been suggested that impaired phagocytosis of the RPE is involved in the progression of non-exudative AMD, but the mechanism is not fully clear. In this study, we investigated the effect of lipid droplet accumulation on RPE function. Compared to young mice, the expression of lipid droplet-associated proteins increased in the RPE-choroidal complex, and lipid droplet in the RPE was observed in aged pigmented mice (12-month-old). Repeated treatment of the photoreceptor outer segment against ARPE-19 resulted in lipid droplets in ARPE-19 cells in vitro. Oleic acid treatment for ARPE-19 cells to form intracellular lipid droplet reduced the POS uptake into the ARPE-19 cells without causing a decrease in cell viability. The suppression of the POS uptake by lipid droplet formation improved by inhibiting lipid droplet formation using triacsin C. Moreover, the amount of intracellular reactive oxygen species was suppressed by the triacsin C treatment. These results indicate that lipid droplet is involved in the RPE dysfunction, and inhibiting lipid droplet formation may be a target for preventing and treating non-exudative AMD.

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“…Under normal circumstances, retinal pigment epithelial cells (RPEs) play a critical role in neutralizing the harmful radicals to maintain a redox homeostasis state in the retina [ 4 ]. Furthermore, RPEs phagocytize toxic lipid–protein aggregates derived from the outer layer of photoreceptors via autophagy [ 6 ]. However, this constant exposure to oxidative stress will eventually shift these RPEs to an exhausted stage, hindering their proper and regular functions [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro

et al. 2022

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Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO3) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO3 injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina’s autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease.

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Autophagy in the retinal pigment epithelium: a new vision and future challenges

Abstract: This article is protected by copyright. All rights reserved LC3B: microtubule-associated protein 1 light chain 3 beta 11-cis RAL: 11-cis retinal mTORC1: Mechanistic target of rapamycin complex 1

Cited by 36 publications

References 128 publications

Activation of autophagy reverses progressive and deleterious protein aggregation in PRPF31 patient‐induced pluripotent stem cell‐derived retinal pigment epithelium cells

Activation of autophagy reverses progressive and deleterious protein aggregation in PRPF31 patient‐induced pluripotent stem cell‐derived retinal pigment epithelium cells

Lipid Droplet Accumulation Promotes RPE Dysfunction

Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro

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