scholarly journals Retbindin: A riboflavin Binding Protein, Is Critical for Photoreceptor Homeostasis and Survival in Models of Retinal Degeneration

2020 ◽  
Vol 21 (21) ◽  
pp. 8083
Author(s):  
Ayse M. Genc ◽  
Mustafa S. Makia ◽  
Tirthankar Sinha ◽  
Shannon M. Conley ◽  
Muayyad R. Al-Ubaidi ◽  
...  
Keyword(s):  
Retinal Disease ◽  
Specific Protein ◽  
Protective Role ◽  
Flavin Mononucleotide ◽  
Disease Genes ◽  
Cellular Mechanisms ◽  
Photoreceptor Outer Segment ◽  
Disease Etiology ◽  
Retinal Degenerations ◽  
Metabolic Dysregulation

The large number of inherited retinal disease genes (IRD), including the photopigment rhodopsin and the photoreceptor outer segment (OS) structural component peripherin 2 (PRPH2), has prompted interest in identifying common cellular mechanisms involved in degeneration. Although metabolic dysregulation has been shown to play an important role in the progression of the disease etiology, identifying a common regulator that can preserve the metabolic ecosystem is needed for future development of neuroprotective treatments. Here, we investigated whether retbindin (RTBDN), a rod-specific protein with riboflavin binding capability, and a regulator of riboflavin-derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is protective to the retina in different IRD models; one carrying the P23H mutation in rhodopsin (which causes retinitis pigmentosa) and one carrying the Y141C mutation in Prph2 (which causes a blended cone-rod dystrophy). RTBDN levels are significantly upregulated in both the rhodopsin (Rho)P23H/+ and Prph2Y141C/+ retinas. Rod and cone structural and functional degeneration worsened in models lacking RTBDN. In addition, removing Rtbdn worsened other phenotypes, such as fundus flecking. Retinal flavin levels were reduced in RhoP23H/+/Rtbdn−/− and Prph2Y141C/+/Rtbdn−/− retinas. Overall, these findings suggest that RTBDN may play a protective role during retinal degenerations that occur at varying rates and due to varying disease mechanisms.

scholarly journals Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ine Strubbe ◽  
Caroline Van Cauwenbergh ◽  
Julie De Zaeytijd ◽  
Sarah De Jaegere ◽  
Marieke De Bruyne ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Somatic Mosaicism ◽  
Retinal Disease ◽  
Hair Follicles ◽  
Disease Genes ◽  
Female Carrier ◽  
Autofluorescence Imaging ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Next Generation Sequencing Ngs

AbstractWe describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.

scholarly journals Loss of melanoregulin (MREG) enhances cathepsin-D secretion by the retinal pigment epithelium

2013 ◽  
Vol 30 (3) ◽  
pp. 55-64 ◽  
Author(s):  
LAURA S. FROST ◽  
VANDA S. LOPES ◽  
FRANK P. STEFANO ◽  
ALVINA BRAGIN ◽  
DAVID S. WILLIAMS ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Cathepsin D ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Disease ◽  
Protective Role ◽  
Phagocytic Cells ◽  
Phagocytic Capacity ◽  
Photoreceptor Outer Segments ◽  
Age Dependent

AbstractCathepsin-D (Cat-D) is a major proteolytic enzyme in phagocytic cells. In the retinal pigment epithelium (RPE), it is responsible for the daily degradation of photoreceptor outer segments (POSs) to maintain retinal homeostasis. Melanoregulin (MREG)-mediated loss of phagocytic capacity has been linked to diminished intracellular Cat-D activity. Here, we demonstrate that loss of MREG enhances the secretion of intermediate Cat-D (48 kDa), resulting in a net enhancement of extracellular Cat-D activity. These results suggest that MREG is required to maintain Cat-D homeostasis in the RPE and likely plays a protective role in retinal health. In this regard, in the Mregdsu/dsu mouse, we observe increased basal laminin. Loss of the Mregdsu allele is not lethal and therefore leads to slow age-dependent changes in the RPE. Thus, we propose that this model will allow us to study potential dysregulatory functions of Cat-D in retinal disease.

scholarly journals Characterization of New Transcripts Enriched in the Mouse Retina and Identification of Candidate Retinal Disease Genes

2004 ◽  
Vol 45 (9) ◽  
pp. 3313 ◽  
Author(s):  
Julie Lord-Grignon ◽  
Nicolas Te´treault ◽  
Alan J. Mears ◽  
Anand Swaroop ◽  
Gilbert Bernier
Keyword(s):  
Retinal Disease ◽  
Mouse Retina ◽  
Disease Genes

scholarly journals Anti-Apoptotic Effects of Carotenoids in Neurodegeneration

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3453 ◽  
Author(s):  
Han-A Park ◽  
Mary Margaret Hayden ◽  
Sydni Bannerman ◽  
Joseph Jansen ◽  
Kristi M. Crowe-White
Keyword(s):  
Cell Death ◽  
Neurodegenerative Disease ◽  
Antioxidant Properties ◽  
Membrane Integrity ◽  
Protective Role ◽  
Brain Cell ◽  
Type I ◽  
Cellular Mechanisms ◽  
Apoptotic Pathways ◽  
Apoptotic Effects

Apoptosis, programmed cell death type I, is a critical part of neurodegeneration in cerebral ischemia, Parkinson’s, and Alzheimer’s disease. Apoptosis begins with activation of pro-death proteins Bax and Bak, release of cytochrome c and activation of caspases, loss of membrane integrity of intracellular organelles, and ultimately cell death. Approaches that block apoptotic pathways may prevent or delay neurodegenerative processes. Carotenoids are a group of pigments found in fruits, vegetables, and seaweeds that possess antioxidant properties. Over the last several decades, an increasing number of studies have demonstrated a protective role of carotenoids in neurodegenerative disease. In this review, we describe functions of commonly consumed carotenoids including lycopene, β-carotene, lutein, astaxanthin, and fucoxanthin and their roles in neurodegenerative disease models. We also discuss the underlying cellular mechanisms of carotenoid-mediated neuroprotection, including their antioxidant properties, role as signaling molecules, and as gene regulators that alleviate apoptosis-associated brain cell death.

scholarly journals Comprehensive Analysis of Photoreceptor Gene Expression and the Identification of Candidate Retinal Disease Genes

Cell ◽  
2001 ◽  
Vol 107 (5) ◽  
pp. 579-589 ◽  
Author(s):  
Seth Blackshaw ◽  
Rebecca E. Fraioli ◽  
Takahisa Furukawa ◽  
Constance L. Cepko
Keyword(s):  
Gene Expression ◽  
Retinal Disease ◽  
Comprehensive Analysis ◽  
Disease Genes

scholarly journals AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

2021 ◽  
Author(s):  
Yunlu Xue ◽  
Sean K. Wang ◽  
Parimal Rana ◽  
Emma R. West ◽  
Christin M. Hong ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Mouse Models ◽  
Retinal Disease ◽  
Disease Genes ◽  
Cone Photoreceptors ◽  
Adeno Associated Virus ◽  
Rescue Effect ◽  
Inherited Retinal Disease ◽  
High Acuity

AbstractRetinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a gene-agnostic therapy, we screened ≈20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

scholarly journals AdipoAtlas: A Reference Lipidome for Human White Adipose Tissue

2021 ◽  
Author(s):  
Mike Lange ◽  
Georgia Angelidou ◽  
Zhixu Ni ◽  
Angela Criscuolo ◽  
Jürgen Schiller ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Metabolic Disorders ◽  
Prognostic Markers ◽  
Absolute Quantification ◽  
Accurate Identification ◽  
Disease Etiology ◽  
Metabolic Dysregulation ◽  
Lipid Molecular Species ◽  
Wide Range

SummaryObesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodelling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodelling at the molecular level, we performed in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. Tissue-tailored preanalytical and analytical workflows allowed accurate identification and semi-absolute quantification of 1636 and 737 lipid molecular species, respectively, and summarized here in a form of human WAT reference lipidome. Deep lipidomic profiling allowed to identify main lipid (sub)classes undergoing depot/phenotype specific remodelling. Furthermore, previously unanticipated diversity of WAT ceramides was uncovered. AdipoAtlas reference lipidome will serve as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.

scholarly journals Prioritization of Retinal Disease Genes: An Integrative Approach

2013 ◽  
Vol 34 (6) ◽  
pp. 853-859 ◽  
Author(s):  
Alex H. Wagner ◽  
Kyle R. Taylor ◽  
Adam P. DeLuca ◽  
Thomas L. Casavant ◽  
Robert F. Mullins ◽  
...  
Keyword(s):  
Retinal Disease ◽  
Integrative Approach ◽  
Disease Genes
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