Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in <i>Rpgr</i> knockout mice

Zhang, Xun; Shahani, Uma; Reilly, James; Shu, Xinhua

doi:10.1002/jcp.28519

Cited by 24 publications

(21 citation statements)

References 44 publications

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“…In inherited retinal degeneration (retinitis pigmentosa, RP), TUDCA prevented photoreceptor degeneration in rpgr knockout mice, an RP mouse model. TUDCA also ameliorated microglial activation and infiltration to the photoreceptor layer [ 14 ]. Activated microglia can produce proinflammatory cytokines, e.g., IL-1β and TNF-α, and TUDCA treatment suppressed inflammasome formation and decreased IL-1β production in the rpgr knockout mouse retinas [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have examined the protective effect of TUDCA against photoreceptor degeneration in a retinitis pigmentosa GTPase regulator ( Rpgr ) knockout mouse model of retinitis pigmentosa. We found that TUDCA attenuated caspase-dependent photoreceptor cell death, inhibited retinal microglial activation, and suppressed inflammasome formation [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Tauroursodeoxycholic Acid Protects Retinal Pigment Epithelial Cells from Oxidative Injury and Endoplasmic Reticulum Stress In Vitro

et al. 2020

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Retinal degeneration is characterized by the dysfunction of retinal cells. Oxidative and endoplasmic reticulum (ER) stress play an important role in the pathogenesis and progression of retinal degeneration. Tauroursodeoxycholic acid (TUDCA) has been demonstrated to have protective effects in in vitro and in vivo retinal degeneration models. To fully understand the molecular mechanisms of TUDCA’s protection, we first treated human retinal pigment epithelial (RPE) cells, ARPE-19, with H2O2 or H2O2 plus TUDCA for 24 h. RPE cells co-exposed to TUDCA had higher cell viability and lower cell death rate compared to cells exposed to H2O2 alone. TUDCA significantly increased antioxidant capacity in H2O2-treated RPE cells by decreasing the generation of reactive oxygen species (ROS) and Malondialdehyde (MDA), upregulating the expression of antioxidant genes, and increasing the generation of glutathione (GSH). TUDCA also inhibited inflammation in H2O2-challenged RPE cells by decreasing the expression of proinflammatory cytokines. Furthermore, TUDCA suppressed thapsigargin-induced ER stress in RPE cells, as demonstrated by decreased the expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and apoptosis. Our present study suggests that TUDCA can protect RPE cells against oxidative damage, inflammation, and ER stress and may benefit patients with retinal degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tauroursodeoxycholic Acid Protects Retinal Pigment Epithelial Cells from Oxidative Injury and Endoplasmic Reticulum Stress In Vitro

et al. 2020

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“…RPGR plays a vital role as a scaffold protein in the regulation of protein trafficking, thus the cargoes can be transported to the outer segments (OSs) of photoreceptors. This trafficking process is controlled by intraflagellar transport complexes and regulated by the RPGR protein complex [29]. The C-terminus of RPGR that contains prenylated site can interact with PDE6δ, INPP5E, and RPGRIP1L, thus regulates ciliary localization of INPP5E [30,31].…”

Section: Discussionmentioning

confidence: 99%

“…But further study should perform to validate the hypothesis in the future. Tauroursodeoxycholic acid (TUDCA) has demonstrated therapeutic potential for RPGR patients by suppressing microglial activation and inflammation and preventing photoreceptor degeneration in Rpgr conditional knockout mice [29]. Adeno-associated viral (AAV) vectors were conducted for RPGR gene therapy by targeting gene expression to both rods and cones in non-human primates [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

A novel missense variant c.G644A (p.G215E) of the RPGR gene in a Chinese family causes X-linked retinitis pigmentosa

Cheng

Zhou

et al. 2019

Bioscience Reports

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The mutations in patients with X-linked retinitis pigmentosa (xlRP) have not been well described in the Chinese population. In the present study, a five-generation Chinese retinitis pigmentosa (RP) family was recruited; targeted next-generation sequencing (TGS) was used to identify causative genes and Sanger sequencing for co-segregation. RNA-seq data analysis and revere transcriptional-polymerase chain reaction (RT-PCR) were applied to investigate gene expression patterns of RP GTPase regulator (RPGR) in human and Rpgr in mouse. A novel, hemizygous, deleterious and missense variant: c.G644A (p.G215E) in the RPGR gene (NM_000328.2) exon 7 of X-chromosome was identified in the proband, which was co-segregated with the clinical phenotypes in this family. RNA-seq data showed that RPGR is ubiquitously expressed in 27 human tissues with testis in highest, but no eye tissues data. Then the expressions for Rpgr mRNA in mice including eye tissues were conducted and showed that Rpgr transcript is ubiquitously expressed very highly in retina and testis, and highly in other eye tissues including lens, sclera, and cornea; and expressed highly in the six different developmental times of retinal tissue. Ubiquitous expression in different tissues from eye and very high expression in the retina indicated that RPGR plays a vital role in eye functions, particularly in retina. In conclusion, our study is the first to indicate that the novel missense variant c.G644A (p.G215E) in the RPGR gene might be the disease-causing mutation in this xlRP family, expanding mutation spectrum. These findings facilitate better understanding of the molecular pathogenesis of this disease; provide new insights for genetic counseling and healthcare.

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“…Expression of nephrocystin-4 (NPHP4), a component of the RPGR unit, was also absent in connecting cilium along with scaffold protein NOD-like receptor family pyrin domain containing receptor 3 (NLRP3) colocalization with microglial neuroinflammation marker ionized calcium binding adaptor molecule 1 (IBA1) in early stages of RPGR knockout mice morphology, a potential contributor to degeneration. Treatment with TUDCA significantly attenuated photoreceptor loss when compared to untreated knockout mice and significantly reduced microglia activation, mimicking morphological similarities to the wild type group [ 114 ]. Lastly, an in vitro model of AMD using retinal pigment epithelial and choroid endothelial cells; TCA treatment maintained tight junction structure and function affected by AMD-induced oxidative stress and inhibited choroidal angiogenesis [ 115 ].…”

Section: Bile Acids In Neurodegenerative Diseasesmentioning

confidence: 99%

Bile Acid Signaling in Neurodegenerative and Neurological Disorders

Grant

DeMorrow

2020

IJMS

113

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Bile acids are commonly known as digestive agents for lipids. The mechanisms of bile acids in the gastrointestinal track during normal physiological conditions as well as hepatic and cholestatic diseases have been well studied. Bile acids additionally serve as ligands for signaling molecules such as nuclear receptor Farnesoid X receptor and membrane-bound receptors, Takeda G-protein-coupled bile acid receptor and sphingosine-1-phosphate receptor 2. Recent studies have shown that bile acid signaling may also have a prevalent role in the central nervous system. Some bile acids, such as tauroursodeoxycholic acid and ursodeoxycholic acid, have shown neuroprotective potential in experimental animal models and clinical studies of many neurological conditions. Alterations in bile acid metabolism have been discovered as potential biomarkers for prognosis tools as well as the expression of various bile acid receptors in multiple neurological ailments. This review explores the findings of recent studies highlighting bile acid-mediated therapies and bile acid-mediated signaling and the roles they play in neurodegenerative and neurological diseases.

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Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in Rpgr knockout mice

Cited by 24 publications

References 44 publications

Tauroursodeoxycholic Acid Protects Retinal Pigment Epithelial Cells from Oxidative Injury and Endoplasmic Reticulum Stress In Vitro

Tauroursodeoxycholic Acid Protects Retinal Pigment Epithelial Cells from Oxidative Injury and Endoplasmic Reticulum Stress In Vitro

A novel missense variant c.G644A (p.G215E) of the RPGR gene in a Chinese family causes X-linked retinitis pigmentosa

Bile Acid Signaling in Neurodegenerative and Neurological Disorders

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