Article
Biochemistry & Molecular Biology
Yujie Dong, Jie Yan, Ming Yang, Wenrong Xu, Zhulin Hu, Francois Paquet-Durand, Kangwei Jiao
Summary: Inherited retinal degeneration (IRD) is a group of blinding diseases caused by gene mutations. Excessive activation of HDAC, PARP, and calpain is linked to photoreceptor loss in IRD. Inhibition of HDAC, PARP, or calpain has shown promise in preventing photoreceptor cell death, but their relationship is still unclear. In this study, organotypic retinal explant cultures from wild-type and rd1 mice were treated with specific inhibitors for HDAC, PARP, and calpain. The results showed that inhibition of HDAC, PARP, or calpain reduced rd1 mouse photoreceptor degeneration, with HDAC inhibitor Vorinostat being the most effective. HDAC inhibition reduced PARP activity but both HDAC and PARP inhibition were needed to reduce calpain activity. Unexpectedly, combined treatment with inhibitors for PARP and calpain or HDAC and calpain did not produce synergistic photoreceptor rescue. These findings suggest that in rd1 photoreceptors, HDAC, PARP, and calpain are part of the same degenerative pathway, activated in a sequence starting with HDAC and ending with calpain.
Article
Biochemistry & Molecular Biology
Jie Yan, Alexander Guenter, Soumyaparna Das, Regine Muehlfriedel, Stylianos Michalakis, Kangwei Jiao, Mathias W. Seeliger, Francois Paquet-Durand
Summary: Inherited retinal degenerations (IRDs) are blinding diseases characterized by progressive loss of photoreceptors. The excessive activation of calpain and poly (ADP-ribose) polymerase (PARP) is associated with the pathology of IRDs. Inhibitors of these enzymes have shown promise in preventing photoreceptor cell death. However, the relationship between calpain and PARP in IRDs is still unclear. In this study, organotypic retinal explant cultures were used to investigate the effects of calpain inhibitors, PARP inhibitors, and voltage-gated Ca2+ channel (VGCC) inhibitors on cell death in IRD mice models. The results suggest that PARP acts upstream of calpain and both enzymes are part of the same degenerative pathway in Pde6b-dependent photoreceptor degeneration. Our findings highlight the potential of targeting PARP for therapeutic interventions in IRD-type diseases.
Article
Neurosciences
Una Greferath, Mario Huynh, Andrew Ian Jobling, Kirstan Anne Vessey, Gene Venables, Denver Surrao, Helen Christine O'Neill, Ioannis J. Limnios, Erica Lucy Fletcher
Summary: Retinitis pigmentosa is a group of inherited retinal degenerations characterized by gradual loss of photoreceptors, ultimately leading to irreversible vision loss. This study focused on analyzing the changes in glial, microglial, and photoreceptor cells in different retinal locations in RCS rats, revealing significant differences in photoreceptor loss between the dorsal and ventral retina. The findings suggest that breakdown of the outer limiting membrane may play a role in exacerbating photoreceptor loss in the ventral retina, highlighting the value of using the RCS rat model for sectorial retinitis pigmentosa.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2021)
Article
Ophthalmology
Yuhong Chen, Jieqiong Chen, Hong Wang, Yang Yu, Wenqiu Wang, Wenjia Liu, Suqin Yu, Yuanyuan Gong, Huixun Jia, Tong Li, Xiaodong Sun
Summary: The prevalence of outer retinal tubulation (ORT) varies among different inherited retinal diseases (IRDs) phenotypes, with the highest prevalence in Bietti crystalline corneoretinal dystrophy (BCD). The presence of choroidal atrophy and inner nuclear layer (INL) cysts may be associated with an increased risk of ORT formation in patients with IRD.
Article
Cell Biology
Mingyu Pan, Yue Yin, Xinxia Wang, Quanyi Wang, Lele Zhang, Haiyang Hu, Chen Wang
Summary: UXT plays a vital role in preventing retinal degeneration and may be a crucial target for retinal degenerative diseases. Loss of UXT leads to hyper-autophagy and massive retinal degeneration.
Article
Biochemistry & Molecular Biology
Javier Martinez-Gonzalez, Angel Fernandez-Carbonell, Antolin Canto, Roberto Gimeno-Hernandez, Inmaculada Almansa, Francisco Bosch-Morell, Maria Miranda, Teresa Olivar
Summary: This study demonstrates alterations in microglia and macroautophagy in an RP mouse model during the early stages of the disease. It suggests that inflammation and macroautophagy processes could be potential treatment alternatives for RP, while chaperone-mediated autophagy could be a therapeutic target in later stages. These findings provide important insights into the pathogenesis of RP and the development of treatment strategies.
Article
Cell Biology
Imen Habibi, Yosra Falfoul, Hoai Viet Tran, Khaled El Matri, Ahmed Chebil, Leila El Matri, Daniel F. Schorderet
Summary: This study identified a new form of digenetic combination in families with autosomal dominant retinal dystrophies, showing that in consanguineous families, autosomal recessive can be transmitted as pseudodominant inheritance in RD patients. The findings further expand our knowledge of pathogenic variants in RD genes.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Anatomy & Morphology
Sohair A. Eltony, Heba S. Mohaseb, Amel A. Ahmed, Manal M. Sayed
Summary: This study aimed to investigate the effect of metformin on the retina of the ENU-induced rat model of RP. The results showed that metformin could reduce retinal degeneration and improve the morphology of glia and blood capillaries. This suggests that metformin has a neuroprotective effect on the retina.
Review
Biology
Arupratan Das, Yoshikazu Imanishi
Summary: This review discusses targets and drug discovery strategies for inherited retinal degeneration using animal models, stem cells, and small molecule screening, with updates on preclinical developments. Inherited retinal degeneration is a group of devastating blinding disorders for which no cures exist. The review also highlights the potential of modulating metabolic pathways and utilizing phenotypic screening in therapeutic approaches, as well as the use of stem cell-based disease models for drug discovery and preclinical development.
Review
Genetics & Heredity
Chitra Kannabiran, Deepika Parameswarappa, Subhadra Jalali
Summary: This review discusses the genetic studies on retinitis pigmentosa in India and neighboring South Asian countries. These populations have been understudied in this aspect, but efforts have been made to identify the genetic characteristics of RP in Indian families and large extended families from Pakistan. The extreme clinical and genetic heterogeneity of RP poses challenges in identifying associated genes and translating research findings for better disease management.
FRONTIERS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Yujie Dong, Wenrong Xu, Yan Li, Chunling Wei, Yunzhang Hu, Zhulin Hu, Francois Paquet-Durand, Kangwei Jiao
Summary: This study investigated the effect of early growth response-1 (EGR1) expression on photoreceptor cell death in rd1 mice and its mechanism of action. The results showed differential expression of ERG1 in rd1 and WT mice and demonstrated the relationship between EGR1 and PARP1. Inhibition of the MAPK/c-Jun pathway reduced the expression of EGR1 and PARP1 and prevented photoreceptor cell death.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Genetics & Heredity
Pankhuri Gupta, Kenji Nakamichi, Alyssa C. C. Bonnell, Ryan Yanagihara, Nick Radulovich, Fuki M. M. Hisama, Jennifer R. R. Chao, Debarshi Mustafi
Summary: Phasing genetic variants is crucial for identifying potential disease-causing variants. Reclassification of variants of uncertain significance (VUS) in autosomal recessive inherited retinal diseases (IRDs) can lead to a genetic diagnosis when combined with familial co-segregation analysis. This study reports four cases where a VUS was found to be trans to a known pathogenic variant through familial co-segregation, resulting in the reclassification of the VUS to likely pathogenic and a genetic diagnosis. Additionally, targeted long-read sequencing was utilized to infer variant phasing in a simplex patient without access to family members for co-segregation analysis. This emerging method provides a solution for cases where genetic testing of family members is unfeasible, allowing for a complete genetic diagnosis.
NPJ GENOMIC MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Natalia Martinez-Gil, Oksana Kutsyr, Agustina Noailles, Laura Fernandez-Sanchez, Lorena Vidal, Xavier Sanchez-Saez, Carla Sanchez-Castillo, Pedro Lax, Nicolas Cuenca, Antonio G. Garcia, Victoria Maneu
Summary: P2X7R and P2X4R play important roles in retinal diseases and their expression increases during disease progression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Keita Sato, Yang Liu, Takahiro Yamashita, Hideyo Ohuchi
Summary: Eyes shut homolog (EYS) mutation causes retinitis pigmentosa type 25 (RP25) with progressive retinal degeneration. In this study, eys-null medaka fish were generated using the CRISPR-Cas9 system, and the roles of EYS in photoreceptor structure and function were examined. The results showed that EYS is required for the regeneration of photoreceptor outer segments, especially cone photoreceptors, and transport of outer segment proteins by regulating actin filaments. Enhanced autophagy may delay the progression of retinal degeneration in the absence of EYS in the medaka retina.
CELL AND TISSUE RESEARCH
(2023)
Review
Genetics & Heredity
Ivan Seah, Debbie Goh, Hwei Wuen Chan, Xinyi Su
Summary: Inherited retinal diseases (IRDs) are a group of diseases that can lead to blindness. Advances in sequencing technologies have improved molecular characterization and genotype-phenotype correlation of IRDs, fueling research into therapeutic development. Non-human primates (NHP) are ideal animal models due to their similarities to humans, but developing NHP disease models for specific IRDs can be challenging. This review discusses current NHP IRD models and their development methods, with a focus on gene-editing technologies.
Review
Biochemistry & Molecular Biology
Roly Megaw, Toby W. Hurd
BIOCHEMICAL SOCIETY TRANSACTIONS
(2018)
Review
Ophthalmology
Emma Pead, Roly Megaw, James Cameron, Alan Fleming, Baljean Dhillon, Emanuele Trucco, Thomas MacGilliuray
SURVEY OF OPHTHALMOLOGY
(2019)
Article
Genetics & Heredity
Petra zur Lage, Fay G. Newton, Andrew P. Jarman
FRONTIERS IN GENETICS
(2019)
Article
Multidisciplinary Sciences
Alyona Keder, Camille Tardieu, Liza Malong, Anastasia Filia, Assel Kashkenbayeva, Fay Newton, Marcos Georgiades, Jonathan E. Gale, Michael Lovett, Andrew P. Jarman, Joerg T. Albert
SCIENTIFIC REPORTS
(2020)
Article
Genetics & Heredity
Zeinab Fadaie, Laura Whelan, Adrian Dockery, Catherina H. Z. Li, L. Ingeborgh van der Born, Carel B. Hoyng, Christian Gilissen, Jordi Corominas, Charlie Rowlands, Roly Megaw, Anne K. Lampe, Frans P. M. Cremers, Gwyneth Jane Farrar, Jamie M. Ellingford, Paul F. Kenna, Susanne Roosing
Summary: Through whole genome sequencing and functional analysis, a branchpoint variant in BBS1 was identified, resulting in non-syndromic RP in four unrelated individuals. This study highlights the importance of analyzing non-coding regions to provide a conclusive molecular diagnosis.
JOURNAL OF MEDICAL GENETICS
(2022)
Review
Biochemistry & Molecular Biology
Gearoid P. Tuohy, Roly Megaw
Summary: Inherited retinal diseases (IRDs) are a leading cause of visual loss in children and young adults, with over 271 gene mutations contributing to retinal dysfunction. While there is no cure, gene therapy, specifically adeno-associated virus two (AAV2)-mediated treatment, has shown promise in treating IRDs like Leber congenital amaurosis. A systematic review of available gene therapy treatments for IRDs revealed modest improvements in visual acuity and significant progress in full-field stimulus testing, indicating a proof-of-principle for gene therapy in treating IRDs.
Review
Endocrinology & Metabolism
Isabel Boden, Miguel O. Bernabeu, Baljean Dhillon, David A. Dorward, Ian MacCormick, Roly Megaw, Claire Tochel
Summary: The study aimed to investigate the association between diabetic retinopathy (DR) and poor COVID-19 prognosis. By searching seven databases and selecting eligible studies, it was found that there is a significant positive correlation between DR and poor outcomes of COVID-19. However, further research is needed to establish the predictive value of DR due to the variability between studies.
DIABETES RESEARCH AND CLINICAL PRACTICE
(2022)
Article
Multidisciplinary Sciences
Wangchu Xiang, Petra zur Lage, Fay G. Newton, Guiyun Qiu, Andrew P. Jarman
Summary: The cilium of Drosophila chordotonal neurons is important for mechanosensory transduction and has a complex structure with different compartments. TRP channels and dynein motor complexes have specific locations during ciliogenesis, and their stable localization depends on docking proteins in the proximal zone.
SCIENTIFIC REPORTS
(2022)
Article
Ophthalmology
H. D. J. Hogg, L. Low, J. E. Self, J. S. Rahi
Summary: The COVID-19 pandemic has negatively impacted the research activities of UK ophthalmologists, resulting in loss of research time, research delays, and funding shortfalls. A substantial proportion of UK ophthalmologists are research active, but 20.4% of those surveyed felt that the pandemic had made research less attractive.
Article
Ophthalmology
Leonardo Lando, Anne Xuan-Lan Nguyen, Randa Tsz Ha Li, Roly Megaw, Baljean Dhillon, Shyamanga Borooah
Summary: This study evaluates anterior segment changes in a L-ORD cohort, finding that the number of long anterior zonules (LAZ) is symmetric and decreases with age.
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY
(2023)
Article
Biology
Emma A. Hall, Dhivya Kumar, Suzanna L. Prosser, Patricia L. Yeyati, Vicente Herranz-Perez, Jose Manuel Garcia-Verdugo, Lorraine Rose, Lisa McKie, Daniel O. Dodd, Peter A. Tennant, Roly Megaw, Laura C. Murphy, Marisa F. Ferreira, Graeme Grimes, Lucy Williams, Tooba Quidwai, Laurence Pelletier, Jeremy F. Reiter, Pleasantine Mill
Summary: By generating mice lacking PCM1, this study reveals the important role of PCM1 and centriolar satellites in ciliogenesis, specifically in motile cilia on ependymal cells. The findings demonstrate that PCM1 is involved in efficient protein trafficking to and from centrioles, including the removal of CP110 and CEP97 to initiate ciliogenesis, and the threshold for ciliogenesis differs between cell types.
Review
Ophthalmology
Frederick R. Burgess, Hildegard Nikki Hall, Roly Megaw
Summary: Genetic eye diseases, a major cause of visual loss in children and adults, have seen significant progress in gene therapies. One therapy has already been licensed and many more are in clinical trials. However, there are still fundamental questions and challenges to overcome in the development of effective gene therapies for these diseases.
ASIA-PACIFIC JOURNAL OF OPHTHALMOLOGY
(2022)
Article
Endocrinology & Metabolism
C. T. Davidson, A. R. Dover, C. M. McVicar, R. Megaw, J. V. Glenn, P. W. F. Hadoke, A. W. Stitt, B. R. Walker
DIABETES & METABOLISM
(2017)