Autophagy, exosomes and drusen formation in age-related macular degeneration

Wang, Ai Ling; Lukas, Thomas J.; Yuan, Ming; Du, Ning; Tso, Mark O.M.; Neufeld, Arthur H.

doi:10.4161/auto.5.4.8163

Cited by 100 publications

(86 citation statements)

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“…At present, it is known that autophagic degradation is involved in several human neurodegenerative diseases [14]. Interestingly, it has been demonstrated that in human AMD donor samples there are accumulations of autophagic markers and decreased lysosomal activity [6,7]. An effective autophagic clearance system has also recently been documented in human RPE cells [4,5,7,13].…”

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

“…: +358-17-162015; FAX: +358-17-162048; email: Kai.Kaarniranta@uef.fi clearance system in aged RPE cells [1]. Recently, it has been documented that in human AMD donor samples and in RPE cell cultures, there are increased levels of autophagic markers and decreased lysosomal activity [4][5][6][7].Eukaryotic cells have two major proteolytic systems for the clearance of proteins: the first is the ubiquitin-proteasome pathway and the second is the vesicle-dependent lysosomal pathway [8]. The ubiquitin-proteasome system recognizes and selectively degrades oxidatively damaged soluble proteins that have not been successfully repaired by molecular chaperones such as heat shock proteins (HSPs) [1].…”

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confidence: 99%

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p62/sequestosome 1 as a regulator of proteasome inhibitor‐induced autophagy in human retinal pigment epithelial cells

KAARNIRANTA

2010

Acta Ophthalmologica

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Purpose:The pathogenesis of age-related macular degeneration involves impaired protein degradation in retinal pigment epithelial (RPE) cells. The ubiquitin-proteasome pathway and the lysosomal pathway including autophagy are the major proteolytic systems in eukaryotic cells. Prior to proteolysis, heat shock proteins (HSPs) attempt to refold stress-induced misfolded proteins and thus prevent the accumulation of cytoplasmic protein aggregates. Recently, p62/sequestosome 1 (p62) has been shown to be a key player linking the proteasomal and lysosomal clearance systems. In the present study, the functional roles of p62 and HSP70 were evaluated in conjunction with proteasome inhibitor-induced autophagy in human RPE cells . Methods: The p62, HSP70, and ubiquitin protein levels and localization were analyzed by western blotting and immunofluorescense. Confocal and transmission electron microscopy were used to detect cellular organelles and to evaluate the morphological changes. The p62 and HSP70 levels were modulated using RNA interference and overexpression techniques. Cell viability was measured by colorimetric assay. Results: Proteasome inhibition evoked the accumulation of perinuclear aggregates that strongly colocalized with p62 and HSP70. The p62 perinuclear accumulation was time-and concentration-dependent after MG-132 proteasome inhibitor loading. The silencing of p62, rather than Hsp70, evoked suppression of autophagy, when related to decreased LC3-II levels after bafilomycin treatment. In addition, the p62 silencing decreased the ubiquitination level of the perinuclear aggregates. Recently, we showed that hsp70 mRNA depletion increased cell death in ARPE-19 cells. Here, we demonstrate that p62 mRNA silencing has similar effects on cellular viability. Conclusions:Our findings open new avenues for understanding the mechanisms of proteolytic processes in retinal cells, and could be useful in the development of novel therapies targeting p62 and HSP70.Age-related macular degeneration (AMD) is the leading cause of blindness of elderly people in the developed countries. The disease affects the macula, which is located in the central area of the retina. Primarily, AMD is characterized by degeneration of the macular retinal pigment epithelial (RPE) cells [1]. The RPE cells take care of the health of rods and cones. Therefore, the degeneration and cell death of RPE cells cause secondary adverse effects on the neural cells, ultimately leading to visual loss. Chronic oxidative stress and inflammation are key factors evoking RPE degeneration and promoting the AMD process [2,3]. One hallmark of AMD is the accumulation of lysosomal lipofuscins, and extracellular drusens between RPE cells and Bruch's membrane. This cargo is a clear evidence of a disturbance in the cellular protein Correspondence to: Kai Kaarniranta, Department of Ophthalmology, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland; Phone.: +358-17-162015; FAX: +358-17-162048; email: Kai.Kaarniranta@uef.fi clearance system in aged RPE cells [1]. Recently,...

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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p62/sequestosome 1 as a regulator of proteasome inhibitor‐induced autophagy in human retinal pigment epithelial cells

KAARNIRANTA

2010

Acta Ophthalmologica

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“…13,14,[28][29][30][31] Recent studies from our laboratory and others indicate a potential role of autophagy either pretreated or not treated with rapamycin (100 nM) for 3 h. Data were analyzed using oneway ANOVA and differences between means were considered statistically significant when P < 0.05. in lipofuscin accumulation, drusen formation, and AMD pathogenesis. 14,22,31 We found that with aging there seemed to be a dramatic increase in LC3, ATG7, and ATG9 in the RPE as well as other retinal layers of non-AMD human donors and our rodent models. It has been reported that autophagic flux increases during aging due to the ROS-induced intracellular burden of damaged organelles and accumulated macromolecules.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD

et al. 2014

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Autophagic dysregulation has been suggested in a broad range of neurodegenerative diseases including agerelated macular degeneration (AMD). To test whether the autophagy pathway plays a critical role to protect retinal pigmented epithelial (RPE) cells against oxidative stress, we exposed ARPE-19 and primary cultured human RPE cells to both acute (3 and 24 h) and chronic (14 d) oxidative stress and monitored autophagy by western blot, PCR, and autophagosome counts in the presence or absence of autophagy modulators. Acute oxidative stress led to a marked increase in autophagy in the RPE, whereas autophagy was reduced under chronic oxidative stress. Upregulation of autophagy by rapamycin decreased oxidative stress-induced generation of reactive oxygen species (ROS), whereas inhibition of autophagy by 3-methyladenine (3-MA) or by knockdown of ATG7 or BECN1 increased ROS generation, exacerbated oxidative stress-induced reduction of mitochondrial activity, reduced cell viability, and increased lipofuscin. Examination of control human donor specimens and mice demonstrated an age-related increase in autophagosome numbers and expression of autophagy proteins. However, autophagy proteins, autophagosomes, and autophagy flux were significantly reduced in tissue from human donor AMD eyes and 2 animal models of AMD. In conclusion, our data confirm that autophagy plays an important role in protection of the RPE against oxidative stress and lipofuscin accumulation and that impairment of autophagy is likely to exacerbate oxidative stress and contribute to the pathogenesis of AMD.

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“…Indeed, it has been proposed that exosomes, small particle released as micro-or nano-particles from many cell types are the origin of drusen, that is, that drusen accumulate due to altered activity of 'para-inflammed' stressed but live RPE cells, rather than represent dead cell waste. 99,100 A protective role for drusen may thus be possible.…”

Section: Pathology Of Macular Degenerationmentioning

confidence: 99%