Pharmacologic activation of autophagy without direct mTOR inhibition as a therapeutic strategy for treating dry macular degeneration

Zhang, Qitao; Presswalla, Feriel; Ali, Robin R.; Zacks, David N.; Thompson, Debra A.; Miller, Jason

doi:10.18632/aging.202974

Cited by 24 publications

(17 citation statements)

References 115 publications

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“…Intriguingly, the mTOR activation is intrinsically involved in the initiation of LC3-conjugation leading to autophagy and LC3-associated phagocytosis ( Figures 4E , 6E ) related to the phagocytosis of the POS, and signaling here comes full circle ( Intartaglia et al, 2021 ). mTOR signaling activation/deactivation equilibrium is of importance in the survival of the retinal pigment epithelium ( Zhang et al, 2021 ) and the reduced gene expression of their component in ABC cells allows them to upregulate the mechanism on demand when the cell needs to, for instance, activate phagocytosis, a process that is not perturbed in this cell line ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

New Retinal Pigment Epithelial Cell Model to Unravel Neuroprotection Sensors of Neurodegeneration in Retinal Disease

et al. 2022

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Retinal pigment epithelial (RPE) cells sustain photoreceptor integrity, and when this function is disrupted, retinal degenerations ensue. Herein, we characterize a new cell line from human RPE that we termed ABC. These cells remarkably recapitulate human eye native cells. Distinctive from other epithelia, RPE cells originate from the neural crest and follow a neural development but are terminally differentiated into “epithelial” type, thus sharing characteristics with their neuronal lineages counterparts. Additionally, they form microvilli, tight junctions, and honeycomb packing and express distinctive markers. In these cells, outer segment phagocytosis, phagolysosome fate, phospholipid metabolism, and lipid mediator release can be studied. ABC cells display higher resistance to oxidative stress and are protected from senescence through mTOR inhibition, making them more stable in culture. The cells are responsive to Neuroprotectin D1 (NPD1), which downregulates inflammasomes and upregulates antioxidant and anti-inflammatory genes. ABC gene expression profile displays close proximity to native RPE lineage, making them a reliable cell system to unravel signaling in uncompensated oxidative stress (UOS) and retinal degenerative disease to define neuroprotection sites.

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Section: Discussionmentioning

confidence: 99%

New Retinal Pigment Epithelial Cell Model to Unravel Neuroprotection Sensors of Neurodegeneration in Retinal Disease

et al. 2022

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“…Whilst this is useful in the early stages of the disease onset, where aggregate accumulation has not progressed, treatment at the later stages could combine the gene therapy with activation of autophagy. A recent paper has identified two FDA approved compounds, which reliably increase autophagic flux in RPE, while preserving RPE cell health and function 86 . Future studies should focus on testing these compounds with respect to prevent aggregate accumulation in PRPF31‐RPE cells and the pharmacogenetic profile (e.g., crossing the blood–retina barrier, biodistribution, etc).…”

Section: Discussionmentioning

confidence: 99%

“…A recent paper has identified two FDA approved compounds, which reliably increase autophagic flux in RPE, while preserving RPE cell health and function. 86 Future studies should focus on testing these compounds with respect to prevent aggregate accumulation in PRPF31-RPE cells and the pharmacogenetic profile (e.g., crossing the blood-retina barrier, biodistribution, etc).…”

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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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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“…Increased oxidative stress in the ageing RPE is known to result in RPE degeneration and accumulation of undigested cellular material as a result of reduced autophagy in these cells [36]. Restoring autophagy is known to decrease oxidative stress and prevent RPE degeneration [36,37]. TFEB regulates transcription of genes involved in the autophagy and lysosomal pathway [14].…”

Section: Discussionmentioning

confidence: 99%

Role of Nuclear Factor of Activated T Cells (NFAT) Pathway in Regulating Autophagy and Inflammation in Retinal Pigment Epithelial Cells

Pan

Ladd

Biswal

et al. 2021

IJMS

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Nuclear factor of activated T cells (NFAT) family of transcription factors are substrates of calcineurin and play an important role in integrating Ca2+ signaling with a variety of cellular functions. Of the five NFAT proteins (NFAT1-5), NFAT1-4 are subject to dephosphorylation and activation by calcineurin, a Ca2+-calmodulin-dependent phosphatase. Increased levels of intracellular Ca2+ activates calcineurin, which in turn dephosphorylates and promotes nuclear translocation of NFAT. We investigated the functions of NFAT proteins in the retinal pigment epithelial cells (RPE). Our results show that NFAT-mediated luciferase activity was induced upon treatment with the bacterial endotoxin, lipopolysaccharide (LPS) and treatment with the NFAT peptide inhibitor, MAGPHPVIVITGPHEE (VIVIT) decreased LPS-induced NFAT luciferase activity. LPS-induced activation of NFAT-regulated cytokines (IL-6 and IL-8) is inhibited by treatment of cells with VIVIT. We also investigated the effects of NFAT signaling on the autophagy pathway. Our results show that inhibition of NFAT with VIVIT in cells deprived of nutrients resulted in cytosolic retention of transcription Factor EB (TFEB), decreased expression of TFEB-regulated coordinated Lysosomal Expression and Regulation CLEAR network genes and decreased starvation-induced autophagy flux in the RPE cells. In summary, these studies suggest that the NFAT pathway plays an important role in the regulation of autophagy and inflammation in the RPE.

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Pharmacologic activation of autophagy without direct mTOR inhibition as a therapeutic strategy for treating dry macular degeneration

Cited by 24 publications

References 115 publications

New Retinal Pigment Epithelial Cell Model to Unravel Neuroprotection Sensors of Neurodegeneration in Retinal Disease

New Retinal Pigment Epithelial Cell Model to Unravel Neuroprotection Sensors of Neurodegeneration in Retinal Disease

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

Role of Nuclear Factor of Activated T Cells (NFAT) Pathway in Regulating Autophagy and Inflammation in Retinal Pigment Epithelial Cells

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