Deletion of autophagy inducer<i>RB1CC1</i>results in degeneration of the retinal pigment epithelium

Yao, Jingyu; Ji, Lin; Khan, Naheed W.; Lin, Cheng‐mao; Mitter, Sayak K.; Boulton, Michael E.; Dunaief, Joshua L.; Klionsky, Daniel J.; Guan, Jun; Thompson, Debra A.; Zacks, David N.

doi:10.1080/15548627.2015.1041699

Cited by 107 publications

(100 citation statements)

References 73 publications

(71 reference statements)

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“…To date, there is strong evidence to support that impaired autophagy in the RPE leads to the accumulation of lipofuscin and a reduced ability to clear intracellular debris,45, 46, 47, 48 and that the activation of autophagy, modulated by the rapamycin-induced inhibition of mTORC1, is able to prevent this harmful AMD-related aging of RPE cells 18, 19, 20. As seen in the expression of LC3B and ATG7, selective markers for autophagic activity, we demonstrate here that this specific mode of autophagy activation significantly reduces CNV.…”

Section: Discussionmentioning

confidence: 99%

Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization

Park

Lee

Choi³

et al. 2017

Molecular Therapy - Nucleic Acids

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Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti-VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week-old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-associated virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were observed in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the reduction of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV.

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Section: Discussionmentioning

confidence: 99%

Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization

Park

Lee

Choi³

et al. 2017

Molecular Therapy - Nucleic Acids

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“…28 Mice were anesthetized with an intraperitoneal injection of ketamine at 80 mg/kg (Hopira, 0409-2051-05) and xylazine at 10 mg/kg ( NAND, 139-236). Body temperature was maintained at 37 C with a heating pad.…”

Section: Electroretinographymentioning

confidence: 99%

Autophagy-mediated catabolism of visual transduction proteins prevents retinal degeneration

Yao

Feathers

et al. 2016

Autophagy

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Autophagy is a lysosomal degradation pathway critical to preventing the accumulation of cytotoxic proteins. Deletion of the essential autophagy gene Atg5 from the rod photoreceptors of the retina (atg5 Drod mouse) results in the accumulation of the phototransduction protein transducin and the degeneration of these neurons. The purpose of this study is to test the hypothesis that autophagic degradation of visual transduction proteins prevents retinal degeneration. Targeted deletion of both Gnat1 (a gene encoding the a subunit of the heterotrimeric G-protein transducin) and Atg5 in the rod photoreceptors resulted in a significantly decreased rate of rod cell degeneration as compared to the atg5Drod mouse retina, and considerable preservation of photoreceptors. Supporting this we used a novel technique to immunoprecipitate green fluorescent protein (GFP)-tagged autophagosomes from the retinas of the GFP-LC3 mice and demonstrated that the visual transduction proteins transducin and ARR/ arrestin are associated with autophagosome-specific proteins. Altogether, this study shows that degradation of phototransduction proteins by autophagy is necessary to prevent retinal degeneration. In addition, we demonstrate a simple and easily reproducible immunoisolation technique for enrichment of autophagosomes from the GFP-LC3 mouse retina, providing a novel application to the study of autophagosome contents across different organs and specific cell types in vivo.

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“…However, the activity of autophagic processes decreases with aging in RPE cells (Viiri et al 2013;Rodríguez-Muela et al 2013;Mitter et al 2014;Toops et al 2015;Yao et al 2015). One explanation for this decreased autophagy might be the accumulation of lipofuscin, a hallmark of aging; this protein is known to suppress lysosomal function and autophagic clearance in RPE cells (Ryhänen et al 2009;Krohne et al 2010;Viiri et al 2013;Mitter et al 2014;Valapala et al 2014;Zhang et al 2015).…”

Section: Discussionmentioning

confidence: 96%

Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis

et al. 2016

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Collagen XVIII has the structural properties of both collagen and proteoglycan. It has been found at the basement membrane/stromal interface where it is thought to mediate their attachment. Endostatin, a proteolytic fragment from collagen XVIII C-terminal end has been reported to possess anti-angiogenic properties. Age-related vision loss in collagen XVIII mutant mice has been accompanied with a pathological accumulation of deposits under the retinal pigment epithelium (RPE). We have recently demonstrated that impaired proteasomal and autophagy clearance are associated with the pathogenesis of age-related macular degeneration. This study examined the staining levels of proteasomal and autophagy markers in the RPE of different ages of the Col18a1 (-/-) mice. Eyes from 3, 6-7, 10-13 and 18 months old mice were enucleated and embedded in paraffin according to the routine protocol. Sequential 5 μm-thick parasagittal samples were immunostained for proteasome and autophagy markers ubiquitin (ub), SQSTM1/p62 and beclin-1. The levels of immunopositivity in the RPE cells were evaluated by confocal microscopy. Collagen XVIII knock-out mice had undergone age-related RPE degeneration accompanied by an accumulation of drusen-like deposits. Ub protein conjugate staining was prominent in both RPE cytoplasm and extracellular space whereas SQSTM1/p62 and beclin-1 stainings were clearly present in the basal part of RPE cell cytoplasm in the Col18a1 (-/-) mice. SQSTM1/p62 displayed mild extracellular space staining. Disturbed proteostasis regulated by collagen XVIII might be responsible for the RPE degeneration, increased protein aggregation, ultimately leading to choroidal neovascularization.

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Deletion of autophagy inducerRB1CC1results in degeneration of the retinal pigment epithelium

Cited by 107 publications

References 73 publications

Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization

Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization

Autophagy-mediated catabolism of visual transduction proteins prevents retinal degeneration

Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis

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