A Frameshift Mutation inRPGRExon ORF15 Causes Photoreceptor Degeneration and Inner Retina Remodeling in a Model of X-Linked Retinitis Pigmentosa

2006 ◽  
Vol 47 (4) ◽  
pp. 1669 ◽  
Author(s):  
William A. Beltran ◽  
Pamela Hammond ◽  
Gregory M. Acland ◽  
Gustavo D. Aguirre
Keyword(s):  
Retinitis Pigmentosa ◽  
Frameshift Mutation ◽  
Photoreceptor Degeneration ◽  
Inner Retina

scholarly journals Ablation of the X-Linked Retinitis Pigmentosa 2 (Rp2) Gene in Mice Results in Opsin Mislocalization and Photoreceptor Degeneration

2013 ◽  
Vol 54 (7) ◽  
pp. 4503 ◽  
Author(s):  
Linjing Li ◽  
Naheed Khan ◽  
Toby Hurd ◽  
Amiya Kumar Ghosh ◽  
Christiana Cheng ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Photoreceptor Degeneration

scholarly journals Carnosic acid slows photoreceptor degeneration in the Pde6brd10 mouse model of retinitis pigmentosa

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Kai Kang ◽  
Matthew J. Tarchick ◽  
Xiaoshan Yu ◽  
Craig Beight ◽  
Ping Bu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinitis Pigmentosa ◽  
Carnosic Acid ◽  
Photoreceptor Degeneration

scholarly journals Retinitis Pigmentosa Results in Neurodegeneration Concomitant With Neuroinflammation, Extracellular Matrix Disorganization and the Upregulation of Neuroprotective Pathways in Glial Cells and Neurons

2020 ◽  
Author(s):  
Christina B. Bielmeier ◽  
Saskia Roth ◽  
Sabrina I. Schmitt ◽  
Stefaniya K. Boneva ◽  
Anja Schlecht ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Molecular Mechanisms ◽  
Genetic Model ◽  
Immunofluorescent Staining ◽  
System Response ◽  
Photoreceptor Degeneration ◽  
The Impact

Abstract BackgroundHereditary retinal degenerations like retinitis pigmentosa (RP) are amongst the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. Here, we in-depth characterized the transgenic VPP mouse model, a genetic model for autosomal dominant RP. MethodsWe examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescent staining and 3D reconstruction. ResultsOne month-old VPP mice showed a significantly higher number of apoptotic photoreceptor cells that resulted in a significantly thinner ONL in three months-old VPP mice, concomitant with an increase in reactivity of microglia and Müller cells. By RNASeq analysis we identified 9,256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, amongst others, dysregulation of TGF-β regulated extracellular matrix organization, factors of the (ocular) immune system/response and apoptosis. ConclusionThe predominant effect pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated and VEGF signaling that were significantly associated with the VPP transgene-induced photoreceptor degeneration. Thus, modulation of these processes might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.

scholarly journals ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure

2018 ◽  
Vol 29 (13) ◽  
pp. 1590-1598 ◽  
Author(s):  
Abigail R. Moye ◽  
Ratnesh Singh ◽  
Victoria A. Kimler ◽  
Tanya L. Dilan ◽  
Daniella Munezero ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Outer Segment ◽  
Photoreceptor Cells ◽  
Visual Response ◽  
Photoreceptor Degeneration ◽  
Progressive Reduction ◽  
Ciliary Protein ◽  
Vertically Aligned ◽  
And Function

The outer segment (OS) of photoreceptor cells is an elaboration of a primary cilium with organized stacks of membranous disks that contain the proteins needed for phototransduction and vision. Though ciliary formation and function has been well characterized, little is known about the role of cilia in the development of photoreceptor OS. Nevertheless, progress has been made by studying mutations in ciliary proteins, which often result in malformed OSs and lead to blinding diseases. To investigate how ciliary proteins contribute to OS formation, we generated a knockout (KO) mouse model for ARL2BP, a ciliary protein linked to retinitis pigmentosa. The KO mice display an early and progressive reduction in visual response. Before photoreceptor degeneration, we observed disorganization of the photoreceptor OS, with vertically aligned disks and shortened axonemes. Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs. On the basis of results from this study, we conclude that ARL2BP is necessary for photoreceptor ciliary doublet formation and axoneme elongation, which is required for OS morphogenesis and vision.

scholarly journals Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations

2016 ◽  
Vol 113 (21) ◽  
pp. E2925-E2934 ◽  
Author(s):  
Xun Sun ◽  
James H. Park ◽  
Jessica Gumerson ◽  
Zhijian Wu ◽  
Anand Swaroop ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Tandem Repeats ◽  
Mutant Mouse ◽  
Retinal Dystrophy ◽  
Retinal Disease ◽  
Pathogenic Mechanism ◽  
Common Disease ◽  
Photoreceptor Degeneration ◽  
Interaction Domain ◽  
Basic Domain

Mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of retinitis pigmentosa, a blinding retinal disease resulting from photoreceptor degeneration. A photoreceptor specific ORF15 variant of RPGR (RPGRORF15), carrying multiple Glu-Gly tandem repeats and a C-terminal basic domain of unknown function, localizes to the connecting cilium where it is thought to regulate cargo trafficking. Here we show that tubulin tyrosine ligase like-5 (TTLL5) glutamylates RPGRORF15 in its Glu-Gly–rich repetitive region containing motifs homologous to the α-tubulin C-terminal tail. The RPGRORF15 C-terminal basic domain binds to the noncatalytic cofactor interaction domain unique to TTLL5 among TTLL family glutamylases and targets TTLL5 to glutamylate RPGR. Only TTLL5 and not other TTLL family glutamylases interacts with RPGRORF15 when expressed transiently in cells. Consistent with this, a Ttll5 mutant mouse displays a complete loss of RPGR glutamylation without marked changes in tubulin glutamylation levels. The Ttll5 mutant mouse develops slow photoreceptor degeneration with early mislocalization of cone opsins, features resembling those of Rpgr-null mice. Moreover TTLL5 disease mutants that cause human retinal dystrophy show impaired glutamylation of RPGRORF15. Thus, RPGRORF15 is a novel glutamylation substrate, and this posttranslational modification is critical for its function in photoreceptors. Our study uncovers the pathogenic mechanism whereby absence of RPGRORF15 glutamylation leads to retinal pathology in patients with TTLL5 gene mutations and connects these two genes into a common disease pathway.

scholarly journals Retinal Ganglion Cell Death as a Late Remodeling Effect of Photoreceptor Degeneration

2019 ◽  
Vol 20 (18) ◽  
pp. 4649 ◽  
Author(s):  
Diego García-Ayuso ◽  
Johnny Di Pierdomenico ◽  
Manuel Vidal-Sanz ◽  
María P. Villegas-Pérez
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Ganglion ◽  
Photoreceptor Degeneration ◽  
Inner Retina ◽  
Retinal Ganglion Cell Death ◽  
Ganglion Cell Death ◽  
Photoreceptor Degenerations

Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially affect rods and cones, situated in the outer retina. For many years it was assumed that these diseases did not spread to the inner retina. However, it is now known that photoreceptor loss leads to an unavoidable chain of events that cause neurovascular changes in the retina including migration of retinal pigment epithelium cells, formation of “subretinal vascular complexes”, vessel displacement, retinal ganglion cell (RGC) axonal strangulation by retinal vessels, axonal transport alteration and, ultimately, RGC death. These events are common to all photoreceptor degenerations regardless of the initial trigger and thus threaten the outcome of photoreceptor substitution as a therapeutic approach, because with a degenerating inner retina, the photoreceptor signal will not reach the brain. In conclusion, therapies should be applied early in the course of photoreceptor degeneration, before the remodeling process reaches the inner retina.

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