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Journal of Neuroinflammation Jul 2023Dysfunction of microglia during aging affects normal neuronal function and results in the occurrence of neurodegenerative diseases. Retinal microglial senescence...
BACKGROUND
Dysfunction of microglia during aging affects normal neuronal function and results in the occurrence of neurodegenerative diseases. Retinal microglial senescence attributes to retinal ganglion cell (RGC) death in glaucoma. This study aims to examine the role of ATP-P2XR in the mediation of microglia senescence and glaucoma progression.
METHODS
Forty-eight participants were enrolled, including 24 patients with primary open-angle glaucoma (POAG) and age-related cataract (ARC) and 24 patients with ARC only. We used ARC as the inclusion criteria because of the availability of aqueous humor (AH) before phacoemulsification. AH was collected and the adenosine triphosphate (ATP) concentration was measured by ATP Assay Kit. The chronic ocular hypertension (COH) mouse model was established by microbead occlusion. Microglia were ablated by feeding PLX5622 orally. Mouse bone marrow cells (BMCs) were prepared and infused into mice through the tail vein for the restoration of microglia function. Western blotting, qPCR and ELISA were performed to analyze protein and mRNA expression in the ocular tissue, respectively. Microglial phenotype and RGC survival were assessed by immunofluorescence. The mitochondrial membrane potential was measured using a JC-1 assay kit by flow cytometry.
RESULTS
ATP concentrations in the AH were increased in older adults and patients with POAG. The expression of P2XR was upregulated in the retinal tissues of mice with glaucoma, and functional enrichment analysis showed that P2XR was closely related to cell aging. Through in vivo and in vitro approaches, we showed that pathological activation of ATP-P2XR induced accelerated microglial senescence through impairing PTEN-induced kinase 1 (PINK1)-mediated mitophagy, which led to RGC damage. Additionally, we found that replacement of senescent microglia in COH model of old mice with BMCs from young mice reversed RGC damage.
CONCLUSION
ATP-P2XR induces microglia senescence by inhibiting PINK1-mediated mitophagy pathway. Specific inhibition of ATP-P2XR may be a fundamental approach for targeted therapy of RGC injury in microglial aging-related glaucoma.
Topics: Mice; Animals; Retinal Ganglion Cells; Microglia; Adenosine Triphosphate; Glaucoma, Open-Angle; Ocular Hypertension; Glaucoma; Disease Models, Animal; Protein Kinases
PubMed: 37525172
DOI: 10.1186/s12974-023-02855-1 -
Journal of Translational Medicine Nov 2023In primary open-angle glaucoma (POAG), lowering intraocular pressure (IOP) is the only proven way of slowing vision loss. Schlemm's canal (SC) is a hybrid vascular and...
BACKGROUND
In primary open-angle glaucoma (POAG), lowering intraocular pressure (IOP) is the only proven way of slowing vision loss. Schlemm's canal (SC) is a hybrid vascular and lymphatic vessel that mediates aqueous humour drainage from the anterior ocular chamber. Animal studies support the importance of SC endothelial angiopoietin-TEK signalling, and more recently TIE1 signalling, in maintaining normal IOP. However, human genetic support for a causal role of TIE1 and TEK signalling in lowering IOP is currently lacking.
METHODS
GWAS summary statistics were obtained for plasma soluble TIE1 (sTIE1) protein levels (N = 35,559), soluble TEK (sTEK) protein levels (N = 35,559), IOP (N = 139,555) and POAG (N = 16,677, N = 199,580). Mendelian randomization (MR) was performed to estimate the association of genetically proxied TIE1 and TEK protein levels with IOP and POAG liability. Where significant MR estimates were obtained, genetic colocalization was performed to assess the probability of a shared causal variant (PP) versus distinct (PP) causal variants underlying TIE1/TEK signalling and the outcome. Publicly available single-nucleus RNA-sequencing data were leveraged to investigate differential expression of TIE1 and TEK in the human ocular anterior segment.
RESULTS
Increased genetically proxied TIE1 signalling and TEK signalling associated with a reduction in IOP (- 0.21 mmHg per SD increase in sTIE1, 95% CI = - 0.09 to - 0.33 mmHg, P = 6.57 × 10, and - 0.14 mmHg per SD decrease in sTEK, 95% CI = - 0.03 to - 0.25 mmHg, P = 0.011), but not with POAG liability. Colocalization analysis found that the probability of a shared causal variant was greater for TIE1 and IOP than for TEK and IOP (PP/(PP + PP) = 0.98 for TIE1 and 0.30 for TEK). In the anterior segment, TIE1 and TEK were preferentially expressed in SC, lymphatic, and vascular endothelium.
CONCLUSIONS
This study provides novel human genetic support for a causal role of both TIE1 and TEK signalling in regulating IOP. Here, combined evidence from cis-MR and colocalization analyses provide stronger support for TIE1 than TEK as a potential IOP-lowering therapeutic target.
Topics: Animals; Humans; Intraocular Pressure; Glaucoma, Open-Angle; Mendelian Randomization Analysis; Angiopoietins
PubMed: 37996923
DOI: 10.1186/s12967-023-04737-9 -
Progress in Retinal and Eye Research Jul 2023Mutations in the gene MYOC account for approximately 5% of cases of primary open angle glaucoma (POAG). MYOC encodes for the protein myocilin, a multimeric secreted... (Review)
Review
Mutations in the gene MYOC account for approximately 5% of cases of primary open angle glaucoma (POAG). MYOC encodes for the protein myocilin, a multimeric secreted glycoprotein composed of N-terminal coiled-coil (CC) and leucine zipper (LZ) domains that are connected via a disordered linker to a 30 kDa olfactomedin (OLF) domain. More than 90% of glaucoma-causing mutations are localized to the OLF domain. While myocilin is expressed in numerous tissues, mutant myocilin is only associated with disease in the anterior segment of the eye, in the trabecular meshwork. The prevailing pathogenic mechanism involves a gain of toxic function whereby mutant myocilin aggregates intracellularly instead of being secreted, which causes cell stress and an early timeline for TM cell death, elevated intraocular pressure, and subsequent glaucoma-associated retinal degeneration. In this review, we focus on the work our lab has conducted over the past ∼15 years to enhance our molecular understanding of myocilin-associated glaucoma, which includes details of the molecular structure and the nature of the aggregates formed by mutant myocilin. We conclude by discussing open questions, such as predicting phenotype from genotype alone, the elusive native function of myocilin, and translational directions enabled by our work.
Topics: Humans; Glaucoma, Open-Angle; Glaucoma; Glycoproteins; Eye Proteins; Trabecular Meshwork
PubMed: 37217093
DOI: 10.1016/j.preteyeres.2023.101188 -
JAMA Ophthalmology Nov 2023
Topics: Humans; Intraocular Pressure; Glaucoma, Open-Angle; Benzoates; beta-Alanine; Ophthalmic Solutions; Ocular Hypertension; Antihypertensive Agents
PubMed: 37971506
DOI: 10.1001/jamaophthalmol.2023.2949 -
Asia-Pacific Journal of Ophthalmology...
Topics: Humans; Intraocular Pressure; Glaucoma, Open-Angle; Benzoates; beta-Alanine; Ocular Hypertension
PubMed: 36650088
DOI: 10.1097/APO.0000000000000553 -
Clinical & Experimental Optometry Mar 2024
Topics: Humans; Glaucoma
PubMed: 38467125
DOI: 10.1080/08164622.2023.2300295 -
European Journal of Pharmacology Sep 2023Glaucoma is a chronic and progressive neurodegenerative disease characterized by the loss of retinal ganglion cells and visual field defects, and currently affects... (Review)
Review
Glaucoma is a chronic and progressive neurodegenerative disease characterized by the loss of retinal ganglion cells and visual field defects, and currently affects around 1% of the world's population. Elevated intraocular pressure (IOP) is the best-known modifiable risk factor and a key therapeutic target in hypertensive glaucoma. The trabecular meshwork (TM) is the main site of aqueous humor outflow resistance and therefore a critical regulator of IOP. Fibrosis, a reparative process characterized by the excessive deposition of extracellular matrix components and contractile myofibroblasts, can impair TM function and contribute to the pathogenesis of primary open-angle glaucoma (POAG) as well as the failure of minimally invasive glaucoma surgery (MIGS) devices. This paper provides a detailed overview of the current anti-fibrotic therapeutics targeting the TM in glaucoma, along with their anti-fibrotic mechanisms, efficacy as well as the current research progress from pre-clinical to clinical studies.
Topics: Humans; Trabecular Meshwork; Glaucoma, Open-Angle; Neurodegenerative Diseases; Intraocular Pressure; Glaucoma; Aqueous Humor
PubMed: 37391006
DOI: 10.1016/j.ejphar.2023.175882 -
Klinische Monatsblatter Fur... Feb 2024Primary open-angle glaucoma is a neurodegenerative disease with progressive chronic optic neuropathy and corresponding visual field defects. In this literature review,... (Review)
Review
Primary open-angle glaucoma is a neurodegenerative disease with progressive chronic optic neuropathy and corresponding visual field defects. In this literature review, we discuss systemic diseases and their mechanism for developing glaucoma, including systemic hypertension and hypotension, diabetes, dyslipidemia, obstructive sleep apnoea syndrome, chronic kidney disease, migraine, and polypharmacy.
Topics: Humans; Glaucoma, Open-Angle; Neurodegenerative Diseases; Glaucoma; Optic Nerve Diseases; Optic Nerve; Intraocular Pressure
PubMed: 38412981
DOI: 10.1055/a-2239-0123 -
Advances in Therapy Oct 2023A clinical trial evaluated ocular hypotensive efficacy and safety of netarsudil 0.02% once daily (QD) relative to ripasudil 0.4% twice daily (BID). (Randomized Controlled Trial)
Randomized Controlled Trial
Phase 3 Clinical Trial Comparing the Safety and Efficacy of Netarsudil to Ripasudil in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: Japan Rho Kinase Elevated Intraocular Pressure Treatment Trial (J-ROCKET).
INTRODUCTION
A clinical trial evaluated ocular hypotensive efficacy and safety of netarsudil 0.02% once daily (QD) relative to ripasudil 0.4% twice daily (BID).
METHODS
This was a single-masked, randomized, phase 3, superiority study. Japanese patients were randomized to either the netarsudil 0.02% group or the ripasudil 0.4% group in a 1:1 ratio and treated for 4 weeks. The primary efficacy variable was mean diurnal intraocular pressure (IOP) (average of diurnal time points at 09:00, 11:00, and 16:00) at Week 4.
RESULTS
A total of 245 patients were included in the primary analysis. At Week 4, least squares (LS) mean of diurnal IOP adjusted for baseline was 15.96 and 17.71 mmHg in the netarsudil 0.02% and ripasudil 0.4% groups, respectively, demonstrating the superiority of netarsudil 0.02% QD over ripasudil 0.4% BID by a margin of - 1.74 mmHg (p < 0.0001). Mean reduction from baseline in mean diurnal IOP at Week 4 was 4.65 and 2.98 mmHg, respectively. Adverse events (AEs) occurred less frequently in netarsudil 0.02% than in ripasudil 0.4%, with the incidence of ocular AEs being 59.8% and 66.7%, respectively. The most frequently reported AE was conjunctival hyperemia in both groups, with an incidence of 54.9% and 62.6%, respectively. No serious eye-related AEs were reported.
CONCLUSION
Netarsudil ophthalmic solution 0.02% dosed QD (p.m.) was well tolerated and more effective in reducing IOP than ripasudil ophthalmic solution 0.4% dosed BID. Netarsudil 0.02% QD may become an important option for the treatment of Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).
TRIAL REGISTRATION
ClinicalTrials.gov identifier, NCT04620135.
Topics: Humans; Intraocular Pressure; rho-Associated Kinases; Glaucoma, Open-Angle; Japan; Ocular Hypertension
PubMed: 37603205
DOI: 10.1007/s12325-023-02550-w -
JAMA Ophthalmology Sep 2023Better understanding of primary open-angle glaucoma (POAG) genetics could enable timely screening and promote individualized disease risk prognostication.
IMPORTANCE
Better understanding of primary open-angle glaucoma (POAG) genetics could enable timely screening and promote individualized disease risk prognostication.
OBJECTIVE
To evaluate phenotypic features across genetic burden for POAG.
DESIGN, SETTING, AND PARTICIPANTS
This was a cross-sectional, population-based study conducted from 2006 to 2010. Included participants were individuals from the UK Biobank aged 40 to 69 years. Individuals with non-POAG forms of glaucoma were excluded from the analysis. Data were statistically analyzed from October 2022 to January 2023.
MAIN OUTCOMES AND MEASURES
POAG prevalence based on structural coding, self-reports, and glaucoma-related traits.
RESULTS
Among 407 667 participants (mean [SD] age, 56.3 [8.1] years; 219 183 majority sex [53.8%]) were 14 171 POAG cases. Area under receiver operating characteristic curve for POAG detection was 0.748 in a model including polygenic risk score (PRS), age, sex, and ancestry. POAG prevalence in the highest decile of PRS was 7.4% (3005 of 40 644) vs 1.3% (544 of 40 795) in lowest decile (P < .001). A 1-SD increase in PRS was associated with 1.74 times higher odds of POAG (95% CI, 1.71-1.77), a 0.61-mm Hg increase in corneal-compensated intraocular pressure (IOP; 95% CI, 0.59-0.64), a -0.09-mm Hg decrease in corneal hysteresis (95% CI, -0.10 to -0.08), a 0.08-mm Hg increase in corneal resistance factor (95% CI, 0.06-0.09), and a -0.08-diopter decrease in spherical equivalent (95% CI, -0.11 to -0.07; P < .001 for all). A 1-SD increase in PRS was associated with a thinning of the macula-region retinal nerve fiber layer (mRNFL) of 0.14 μm and macular ganglion cell complex (GCC) of 0.26 μm (P < .001 for both). In the subset of individuals with fundus photographs, a 1-SD increase in PRS was associated with 1.42 times higher odds of suspicious optic disc features (95% CI, 1.19-1.69) and a 0.013 increase in cup-disc ratio (CDR; 95% CI, 0.012-0.014; P < .001 for both). A total of 22 of 5193 fundus photographs (0.4%) in decile 10 had disc hemorrhages, and 27 of 5257 (0.5%) had suspicious optic disc features compared with 9 of 5158 (0.2%) and 10 of 5219 (0.2%), respectively, in decile 1 (P < .001 for both). CDR in decile 10 was 0.46 compared with 0.41 in decile 1 (P < .001).
CONCLUSION AND RELEVANCE
Results suggest that PRS identified a group of individuals at substantially higher risk for POAG. Higher genetic risk was associated with more advanced disease, namely higher CDR and corneal-compensated IOP, thinner mRNFL, and thinner GCC. Associations with POAG PRS and corneal hysteresis and greater prevalence of disc hemorrhages were identified. These results suggest that genetic risk is an increasingly important parameter for risk stratification to consider in clinical practice.
Topics: Humans; Middle Aged; Cross-Sectional Studies; Glaucoma, Open-Angle; Cornea; Glaucoma; Hemorrhage
PubMed: 37589995
DOI: 10.1001/jamaophthalmol.2023.3645