Article
Cell Biology
Eunice Sze Yin Ng, Nermin Kady, Jane Hu, Arpita Dave, Zhichun Jiang, Jacqueline Pei, Michael B. Gorin, Anna Matynia, Roxana A. Radu
Summary: This study found that RPE cells from STGD1 patients exhibited reduced ABCA4 protein and activity, leading to intracellular lipofuscin accumulation and increased complement C3 activity, ultimately causing cell damage and death.
Article
Biochemistry & Molecular Biology
Alexey N. Semenov, Eugene G. Maksimov, Anastasia M. Moysenovich, Marina A. Yakovleva, Georgy V. Tsoraev, Alla A. Ramonova, Evgeny A. Shirshin, Nikolai N. Sluchanko, Tatiana B. Feldman, Andrew B. Rubin, Mikhail P. Kirpichnikov, Mikhail A. Ostrovsky
Summary: Protein-mediated delivery of zeaxanthin using BmCBP-ZEA can suppress photoinducible oxidative stress in RPE cells caused by irradiation of lipofuscin with intense white light. In this study, we used fluorescence lifetime imaging to observe the changes in lipofuscin granules in ARPE-19 cell culture before and after white light irradiation, with and without the addition of BmCBP-ZEA. We found that after irradiation, the average fluorescence lifetime of lipofuscin significantly increased, while the presence of BmCBP-ZEA at 200 nM concentration suppressed the increase in lipofuscin fluorescence lifetime, indicating approximately 35% inhibition of oxidative stress. This phenomenon indirectly demonstrates the effectiveness of protein-mediated carotenoid delivery into pigment epithelium cells.
Article
Biochemistry & Molecular Biology
Marina Yakovleva, Alexander Dontsov, Natalia Trofimova, Natalia Sakina, Alexey Kononikhin, Arseny Aybush, Alexander Gulin, Tatiana Feldman, Mikhail Ostrovsky
Summary: Researchers have found that there is a significant increase in bisretinoid oxidation products in the RPE cells of AMD patients, and these products contain cytotoxic carbonyls, which may contribute to the pathogenesis of AMD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Yuan Fang, Tatjana Taubitz, Alexander Tschulakow, Peter Heiduschka, Grzegorz Szewczyk, Michael Burnet, Tobias Peters, Antje Biesemeier, Tadeusz Sarna, Ulrich Schraermeyer, Sylvie Julien-Schraermeyer
Summary: Remofuscin reverses lipofuscin accumulation in aged RPE cells and is non-cytotoxic in aged SD mouse RPE cells. In a mouse model of advanced SD, a single injection of Remofuscin removes lipofuscin and rescues retinal degeneration, accompanied by improvement in retinal function. The mechanism of lipofuscinolysis may involve reactive oxygen species generated by Remofuscin.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Hye Jin Kim, Diego Montenegro, Jin Zhao, Janet R. Sparrow
Summary: The retina and retinal pigment epithelial cells are exposed to visible light, oxygen-rich, and accumulate photoreactive molecules. These molecules, known as bisretinoids, are generated as a byproduct of vitamin A aldehyde activity and can cause reactive oxygen species, leading to photo-oxidation and photolysis. Bisretinoids accumulate in RPE cells with age and are implicated in retinal disease.
Article
Biochemistry & Molecular Biology
Tatiana Feldman, Dmitriy Ostrovskiy, Marina Yakovleva, Alexander Dontsov, Sergey Borzenok, Mikhail Ostrovsky
Summary: This study found that the bisretinoid oxidation and degradation products in lipofuscin granules from retinal pigment epithelium (RPE) cells have a damaging effect on the RPE cell in the absence of light. These products can be considered as an aggravating factor in age-related macular degeneration progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Tongzhou Xu, Laurie L. Molday, Robert S. Molday
Summary: N-Ret-PE, a crucial molecule in the visual cycle and visual pigment photoregeneration, can form toxic di-retinoids if not removed by ABCA4. Mutations in ABCA4 cause Stargardt disease, which is associated with the accumulation of di-retinoids and vision loss. This study investigates the factors affecting N-Ret-PE formation and identifies key amino acid residues involved in its interaction with ABCA4.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Medicine, General & Internal
Hung-Da Chou, Yih-Shiou Hwang, Kuan-Jen Chen, Wei-Chi Wu, Laura Liu, Shyh-Tyan Ou, Webber Liao, Cheng-Chi Wang, Tom Lin, Chi-Chun Lai
Summary: This study found that age-related macular degeneration (AMD) associated with ABCA4 variants is characterized by the accumulation of visual cycle-byproduct lipofuscin. Reducing retinol-binding protein 4 (RBP4) may reduce lipofuscin production. The study also found that higher levels of RBP4 are associated with the severity of AMD.
Article
Multidisciplinary Sciences
Patty P. A. Dhooge, Esmee H. Runhart, Catherina H. Z. Li, Corrie M. de Kat Angelino, Carel B. Hoyng, Renate G. van der Molen, Anneke den Hollander
Summary: The study did not find elevated systemic complement levels in STGD1 patients compared to age and sex matched controls, and it was not associated with disease severity. It is hypothesized that complement activation in STGD1 is more likely a local process.
Article
Multidisciplinary Sciences
Yanan Lyu, Alexander V. Tschulakow, Kun Wang, Douglas E. Brash, Ulrich Schraermeyer
Summary: Age-related macular degeneration, Stargardt disease, and their Abca4(-/-) mouse model are characterized by accelerated accumulation of lipofuscin in the retinal pigment epithelium (RPE). In this study, it is shown that the RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which are associated with melanolipofuscin granules. Intravitreal injection of reactive oxygen species (ROS) or nitric oxide (NO) decreases TLM-related lipofuscin in melanolipofuscin granules in pigmented mice but not in albino mice. Exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albino mice. Melanin chemiexcitation is important for safe photoreceptor disc turnover.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Melita Kaltak, Zelia Corradi, Rob W. J. Collin, Jim Swildens, Frans P. M. Cremers
Summary: This study investigated the impact of synonymous and missense variants in ABCA4 on pre-mRNA splicing. It identified 16 out of 18 analyzed variants that caused splice aberrations. These findings highlight the causal role of coding ABCA4 variants in splicing abnormalities, improving the severity assessment of missense and synonymous ABCA4 variants, and guiding new treatment strategies for STGD1.
HUMAN MOLECULAR GENETICS
(2023)
Article
Medicine, Research & Experimental
Da Sun, Wenyu Sun, Song-Qi Gao, Jonathan Lehrer, Amirreza Naderi, Cheng Wei, Sangjoon Lee, Andrew L. Schilb, Josef Scheidt, Ryan C. Hall, Elias I. Traboulsi, Krzysztof Palczewski, Zheng-Rong Lu
Summary: Stargardt disease, caused by mutations in ABCA4 gene, is a common form of inherited retinal genetic disorders. Gene therapy using self-assembly nanoparticles shows promising results in treating this disease by producing specific and prolonged expression of ABCA4, reducing the accumulation of toxic substances in the eye.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2022)
Editorial Material
Endocrinology & Metabolism
Zhongjie Fu, Lois E. H. Smith
Summary: Pathologic angiogenesis in eye diseases leading to blindness can be attributed to cell senescence, as demonstrated by the bioinformatics study conducted by Crespo-Garcia, Tsuruda, and Dejda. Their findings were validated in human and mouse retina models, where clearance of senescent cells effectively suppressed neovessel growth.
TRENDS IN ENDOCRINOLOGY AND METABOLISM
(2021)
Article
Geriatrics & Gerontology
Nan Su, Uwe Hansen, Tanja Plagemann, Karin Gaeher, M. Dominik Leclaire, Jeannette Konig, Annika Hoehn, Tilman Grune, Constantin E. Uhlig, Nicole Eter, Peter Heiduschka
Summary: LF injection into the subretinal space of mice leads to activation and migration of microglial cells, increased expression of inflammatory cytokines, and gradual degradation of RPE cells. These features are consistent with those found in an aging retina, suggesting that LF injection could serve as a model for intermediate and late AMD.
Article
Ophthalmology
Rodrigo A. Brant Fernandes, Fernando H. Lojudice, Lucas Zago Ribeiro, Natasha Ferreira Santos da Cruz, Murilo Ubukata Polizelli, Priscila C. Cristovam, Francesco Innocenti, Lisangela Morimoto, Octaviano Magalhaes, Juliana Maria Ferraz Sallum, Fernando Marcondes Penha, Mari C. Sogayar, Rubens Belfort, Mauricio Maia
Summary: This study aimed to assess the safety of injecting human embryonic stem cell retinal pigment epithelial cells for treating Stargardt disease. The results showed that this surgical procedure was feasible and safe, without any adverse effects such as cellular migration, rejection, inflammation, or tumor development.
RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES
(2023)
Article
Neurosciences
Rikard Frederiksen, Ala Morshedian, Sonia A. Tripathy, Tongzhou Xu, Gabriel H. Travis, Gordon L. Fain, Alapakkam P. Sampath
Summary: Rod photoreceptors can become saturated by bright background light, but recent experiments have shown that they can also recover sensitivity and maintain responses even under prolonged exposure to bright light. The reduction of translocation of G protein transducin in transgenic mice may affect the recovery ability, and a novel mechanism of visual-pigment regeneration within the rod itself enables them to remain responsive. This allows rods to avoid extended closure of transduction channels, which could lead to photoreceptor degeneration.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Sheetal Uppal, Sergey A. Dergunov, Weiyu Zhang, Susan Gentleman, T. Michael Redmond, Eugene Pinkhassik, Eugenia Poliakov
Summary: Research has shown the important role of xanthophylls in human vision and their potential impact on antioxidant response. They offer benefits for preventing age-related macular degeneration and alleviating Alzheimer's disease symptoms.
Article
Biochemistry & Molecular Biology
Olga A. Postnikova, Sheetal Uppal, Weiliang Huang, Maureen A. Kane, Rafael Villasmil, Igor B. Rogozin, Eugenia Poliakov, T. Michael Redmond
Summary: The SARS-CoV-2 Spike glycoprotein has acquired a unique insert sequence that could affect virus spread and infection mechanisms, prompting further investigation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Saumil Sethna, Patrick A. Scott, Arnaud P. J. Giese, Todd Duncan, Xiaoying Jian, Sheikh Riazuddin, Paul A. Randazzo, T. Michael Redmond, Steven L. Bernstein, Saima Riazuddin, Zubair M. Ahmed
Summary: The research demonstrates the role of CIB2 in regulating the Rheb-mTORC1 signaling axis and autophagy in AMD. Molecular deficits and pathologies related to AMD were observed in Cib2 mutant mice and dry-AMD patient samples.
NATURE COMMUNICATIONS
(2021)
Article
Neurosciences
Ala Morshedian, Gabriela Sendek, Sze Yin Ng, Kimberly Boyd, Roxana A. Radu, Mingyao Liu, Nikolai O. Artemyev, Alapakkam P. Sampath, Gordon L. Fain
Summary: The high sensitivity of night vision depends on the regulation of intracellular cGMP concentration. A mutation in the PDEA gene reduces PDEA and PDEB expression, resulting in larger, more sensitive, and slower responses in rod photoreceptors. However, the reproducibility of the responses is significantly decreased. This study highlights the importance of PDE expression in maintaining the constancy of rod response.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Chendong Pan, Kalpita Banerjee, Guillermo L. Lehmann, Dena Almeida, Katherine A. Hajjar, Ignacio Benedicto, Zhichun Jiang, Roxana A. Radu, David H. Thompson, Enrique Rodriguez-Boulan, Marcelo M. Nociari
Summary: Lipofuscin granules contain mixtures of cross-linked proteins and lipids, with retinal lipofuscin being unique in its lipid-rich composition. These granules can cause lysosome swelling and trigger inflammation, potentially leading to cell death. This mechanism may provide therapeutic targets for diseases associated with lipofuscin accumulation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biology
Saumil Sethna, Wadih M. Zein, Sehar Riaz, Arnaud Pj Giese, Julie M. Schultz, Todd Duncan, Robert B. Hufnagel, Carmen C. Brewer, Andrew J. Griffith, T. Michael Redmond, Saima Riazuddin, Thomas B. Friedman, Zubair M. Ahmed
Summary: Usher syndrome type I is a rare genetic disorder characterized by deafness, vestibular areflexia, and progressive retinal degeneration. A specific gene variant is prevalent in Ashkenazi Jews and accounts for a majority of USH1 cases. Studies in mouse models have shown similar visual deficits, suggesting potential therapeutic targets for preserving vision in USH1F patients.
Article
Biochemistry & Molecular Biology
Ailis L. Moran, Stephen P. Carter, Joanna J. Kaylor, Zhichun Jiang, Sanne Broekman, Eugene T. Dillon, Alicia Gomez Sanchez, Sajal K. Minhas, Erwin van Wijk, Roxana A. Radu, Gabriel H. Travis, Michelle Carey, Oliver E. Blacque, Breandan N. Kennedy
Summary: The study reveals the importance of Rab28 in regulating both dawn and dusk peaks of outer segment phagocytosis (OSP). Loss of Rab28 leads to dysregulation of factors associated with OSP and perturbs the visual cycle. Transgenic overexpression of Rab28 in zebrafish cones rescues the OSP defect, highlighting the role of Rab28 in regulating OSP.
Article
Ophthalmology
Anna Matynia, Jun Wang, Sangbae Kim, Yumei Li, Anupama Dimashkie, Zhichun Jiang, Jane Hu, Samuel P. Strom, Roxana A. Radu, Rui Chen, Michael B. Gorin
Summary: Modern molecular genetics has greatly advanced gene discovery, genetic diagnoses, and precision medicine. However, up to half of Mendelian genetic disorders still lack disease-causing variants, limiting the benefits for many patients. This study used patient-derived induced pluripotent stem (iPS) cells and transcriptomics to investigate unsolved ABCA4 alleles in Stargardt disease patients. The results suggest that missense variants expressed at high levels have more severe outcomes, and mitochondrial membrane biodynamics and the unfolded protein response pathway may be relevant in Stargardt disease.
TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
(2022)
Article
Cell Biology
Eunice Sze Yin Ng, Nermin Kady, Jane Hu, Arpita Dave, Zhichun Jiang, Jacqueline Pei, Michael B. Gorin, Anna Matynia, Roxana A. Radu
Summary: This study found that RPE cells from STGD1 patients exhibited reduced ABCA4 protein and activity, leading to intracellular lipofuscin accumulation and increased complement C3 activity, ultimately causing cell damage and death.
Article
Multidisciplinary Sciences
Samuel William, Todd Duncan, T. Michael Redmond
Summary: This study demonstrates that pretreatment of ARPE-19 cells with sterculic acid, an inhibitor of the enzyme SCD, can prevent fenretinide-induced apoptosis. Sterculic acid shows antioxidant and anti-inflammatory effects, making it a potential therapeutic agent.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Sheetal Uppal, Olga Postnikova, Rafael Villasmil, Igor B. Rogozin, Alexander V. Bocharov, Thomas L. Eggerman, Eugenia Poliakov, T. Michael Redmond
Summary: Here, we provide evidence that LDLR plays a key role in the caveolae-mediated endocytosis pathway for SARS-CoV-2 virus internalization in ARPE-19 cells. Blocking ACE2 or cholesterol-rich lipid raft proteins did not prevent infection, while inhibition of cholesterol homeostasis using cyclodextrins and 25-HC reduced pseudovirion infection. Clathrin-dependent and flotillin-dependent rafts were not involved, but dynamin and caveolin-1 were found to be essential for virus entry. Furthermore, LDLR antibodies and siRNA-mediated knockdown of LDLR decreased pseudovirion infection. Therefore, we conclude that SARS-CoV-2 virus internalization in ARPE-19 cells primarily involves LDLR through a dynamin-dependent process.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Meeting Abstract
Ophthalmology
Rikard Frederiksen, Ala Morshedian, Sonia A. Tripathy, Tongzhou Xu, Gabriel H. Travis, Gordon L. Fain, Alapakkam P. Sampath
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2021)
Meeting Abstract
Ophthalmology
Ailis Moran, Stephen P. Carter, Joanna J. Kaylor, Roxana A. Radu, Alicia Gomez Sanchez, Gabriel H. Travis, Oliver E. Blacque, Breandan N. Kennedy
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2021)