α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease

Baksi, Shounak; Singh, Neena

doi:10.1038/s41598-017-12862-x

Cited by 49 publications

(45 citation statements)

References 56 publications

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“…Proteins transferred to a PVDF membrane were probed with specific antibodies and developed by chemiluminescence as described (Baksi and Singh, 2017). Quantification of protein bands was performed by densitometry using UN-SCANT-IT (version6.1) software (Silk Scientific) and represented graphically.…”

Section: Methodsmentioning

confidence: 99%

Prion protein modulates iron transport in the anterior segment: Implications for ocular iron homeostasis and prion transmission

Ashok

Karmakar

Chandel

et al. 2018

Experimental Eye Research

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Iron is an essential biometal in the aqueous humor, the principal source of nutrients for the avascular cornea and the lens. Here, we explored whether the ciliary body (CB), the source of aqueous humor, transports iron, and if the prion protein (PrPC) facilitates this process as in the outer retina. Using a combination of human, bovine, and mouse eyes as models, we report the expression of iron export proteins ferroportin and ceruloplasmin, and major iron uptake and storage proteins transferrin, transferrin receptor, and ferritin in the ciliary epithelium, indicating active exchange of iron at this site. Ferroportin and transferrin receptor are also expressed in the corneal endothelium. However, the relative expression of iron export and uptake proteins suggests export from the ciliary epithelium and import by corneal endothelium. In addition, abundant expression of PrPC, a ferrireductase that facilitates iron transport, is noted in pigmented and non-pigmented epithelium of the CB, posterior pigmented epithelium of the iris, corneal endothelium and epithelium, and lens epithelium. Notably, majority of PrPC in the ciliary epithelium is cleaved at the β-site as in retinal pigment epithelial cells, suggesting a role in iron transport. Most of the PrPC in the cornea, however, is full-length, and susceptible to aggregation by intracerebrally inoculated PrP-scrapie, an infectious conformation of PrPC responsible for human and animal prion disorders. Soluble PrPC is present in the aqueous and vitreous humor, a provocative observation with significant implications. Together, these observations suggest independent cycling of iron in the anterior segment, and a prominent role of PrPC in this process. Aggregation of PrPC in the cornea of PrP-scrapie-infected animals raises the alarming possibility of transmission of animal prions through corneal abrasions.

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Section: Methodsmentioning

confidence: 99%

Prion protein modulates iron transport in the anterior segment: Implications for ocular iron homeostasis and prion transmission

Ashok

Karmakar

Chandel

et al. 2018

Experimental Eye Research

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“…As long-lived proteins, including ferritin, are degraded in the lysosome, rescue of lysosomal function by Synucleozid may account, in part, for reduction of ferritin levels. In support of this notion, a study in α-synuclein −/− mice showed that α-synuclein impaired ferritinophagy and conversely that elimination of α-synuclein reduced ferritin levels (35).…”

Section: Resultsmentioning

confidence: 93%

Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA

Zhang

Park

Zhang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson’s disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5′ untranslated region (5′ UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5′ UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound’s selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies.

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“…Ferritinophagy plays an important role in some physiological processes such as erythropoiesis . When ferritinophagy is deregulated, the abnormal iron balance leads to oxidative stress and pathological changes including neurodegenerative diseases …”

Section: Ferritinophagy Induction By Artesunatementioning

confidence: 99%

“…133 When ferritinophagy is deregulated, the abnormal iron balance leads to oxidative stress and pathological changes 134 including neurodegenerative diseases. 135 Yang et al 63 reported that, in human cervical cancer, ART accumulates in cellular lysosomes and decreases the levels of ferritin through the activation of lysosomes instead of proteasomes (Figure 4). In the presence of the autophagy inhibitors CQ or bafilomycin, ART-induced ferritin degradation is completely blocked, indicating the existence of ferritinophagy.…”

Section: Ferritinophagy Induction By Artesunatementioning

confidence: 99%

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

Sun

Yan

Zou

et al. 2019

Medicinal Research Reviews

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Artemisinin and its derivatives, with their outstanding clinical efficacy and safety, represent the most effective and impactful antimalarial drugs. Apart from its antimalarial effect, artemisinin has also been shown to exhibit selective anticancer properties against multiple cancer types both in vitro and in vivo. Specifically, our previous studies highlighted the therapeutic effects of artemisinin on autophagy regulation. Autophagy is a well‐conserved degradative process that recycles cytoplasmic contents and organelles in lysosomes to maintain cellular homeostasis. The deregulation of autophagy is often observed in cancer cells, where it contributes to tumor adaptation to nutrient‐deficient tumor microenvironments. This review discusses recent advances in the anticancer properties of artemisinin and its derivatives via their regulation of autophagy, mitophagy, and ferritinophagy. In particular, we will discuss the mechanisms of artemisinin activation in cancer and novel findings regarding the role of artemisinin in regulating autophagy, which involves changes in multiple signaling pathways. More importantly, with increasing failure rates and the high cost of the development of novel anticancer drugs, the strategy of repurposing traditional therapeutic Chinese medicinal agents such as artemisinin to treat cancer provides a more attractive alternative. We believe that the topics covered here will be important in demonstrating the potential of artemisinin and its derivatives as safe and potent anticancer agents.

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α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: Implications for retinal iron dyshomeostasis in Parkinson’s disease

Cited by 49 publications

References 56 publications

Prion protein modulates iron transport in the anterior segment: Implications for ocular iron homeostasis and prion transmission

Prion protein modulates iron transport in the anterior segment: Implications for ocular iron homeostasis and prion transmission

Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

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