ABSTRACT
Vacuolar protein sorting 35 (VPS35), the core component of the retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson's disease (PD). Impaired vision is a common non-motor manifestation of PD. Here, we show mouse retinas with VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant with the emergence of Lewy body-like inclusions and phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal VPS35-deficient rods accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, we uncover a protein network of VPS35 and its interaction with HSC70. VPS35 deficiency promotes sequestration of HSC70 and P-αSyn aggregation in late endosomes. Microglia which engulf lipofuscins and P-αSyn aggregates are activated, displaying autofluorescence, observed as bright dots in fundus imaging of live animals, coinciding with pathology onset and progression. The Rod∆Vps35 mouse line is a valuable tool for further mechanistic investigation of αSyn lesions and retinal degenerative diseases.
Subject(s)
Retinal Degeneration , Vesicular Transport Proteins , alpha-Synuclein , Animals , alpha-Synuclein/metabolism , alpha-Synuclein/genetics , Vesicular Transport Proteins/metabolism , Vesicular Transport Proteins/genetics , Mice , Retinal Degeneration/genetics , Retinal Degeneration/metabolism , Retinal Degeneration/pathology , Retinal Rod Photoreceptor Cells/metabolism , Retinal Rod Photoreceptor Cells/pathology , Endosomes/metabolism , Microglia/metabolism , Microglia/pathology , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Retina/metabolism , Retina/pathology , Mice, Knockout , Disease Models, Animal , Humans , Synapses/metabolism , Synapses/pathology , MaleABSTRACT
To identify the factors associated with the surgical outcomes of Baerveldt glaucoma implant (BGI) for open-angle glaucoma (OAG), the medical records of 51 consecutive OAG patients (age, 43-91 years) who underwent BGI were retrospectively reviewed (median follow-up, 21.7 months). Surgical success was defined as the following postoperative intraocular pressures (IOPs, mmHg): (A) 6 ≤ IOP ≤ 21; (B) 6 ≤ IOP ≤ 18; and (C) 6 ≤ IOP ≤ 15 without loss of light perception or additional glaucoma surgery. Univariate analysis showed that age (all criteria), glaucoma type (criterion C), and preoperative IOP (criteria A and B) were the candidate factors (P < 0.20). When the patients were divided into two groups according to median age (72 years), the success probability was higher in the older group for criteria B (P = 0.047) and C (P = 0.02), and the postoperative IOP was lower in the older group 1-year post-surgery (P = 0.002). Furthermore, the multivariate Cox proportional hazards model revealed that older age was independently associated with surgical success for criteria B (relative risk [RR], 0.94; P = 0.02) and C (RR, 0.94; P = 0.01). In conclusion, older age is a factor associated with the surgical success of BGI for OAG.
Subject(s)
Glaucoma, Open-Angle/surgery , Glaucoma/surgery , Postoperative Complications/surgery , Adult , Aged , Aged, 80 and over , Follow-Up Studies , Humans , Intraocular Pressure , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Neurotrophic keratopathy (NK) is a rare degenerative corneal disease caused by damage to the trigeminal nerve. We hereby describe a severe case with bilateral corneal perforation due to leprosy (Hansen's disease)-associated NK. CASE PRESENTATION: An 89-year-old man with a history of leprosy treated 40 years previously in our sanatorium developed bilateral corneal perforation due to NK. He had a history of bilateral persistent epithelial defects and bacterial keratitis. Although epithelialization was obtained with the use of autologous serum eye drops, progressive corneal thinning concomitant with stromalysis led to bilateral perforation. Over one month treatment with topical antibiotics, anti-inflammatory and lubricants resulted in healing of the epithelial defects and corneal perforations. A Cochet-Bonnet esthesiometer demonstrated a total absence of corneal sensation in both eyes. CONCLUSIONS: The present case indicated the irreversible nerve damage due to leprosy that had been cured 23 years ago, which can progress over the years and cause bilateral corneal perforations.
Subject(s)
Corneal Dystrophies, Hereditary , Corneal Perforation , Keratitis , Leprosy , Trigeminal Nerve Diseases , Aged, 80 and over , Corneal Perforation/diagnosis , Corneal Perforation/etiology , Humans , Keratitis/diagnosis , Keratitis/etiology , Male , Trigeminal Nerve Diseases/complications , Trigeminal Nerve Diseases/diagnosisABSTRACT
Elevated intraocular pressure (IOP) is a significant risk factor for vision loss due to glaucoma, which is a major cause of blindness worldwide. Glaucoma filtration surgery (GFS) is an important method to reduce IOP by guidance of aqueous humor into a newly built filtration bleb in the conjunctiva; management of the wound healing mechanism is essential for the success of GFS. Here, we investigated the roles of interleukin (IL)-6 family members during the wound healing process after GFS. At the surgical site, the expression levels of genes encoding IL-6, oncostatin M (OSM), their receptors, and collagen I were elevated at 3 h after GFS, whereas the levels of genes encoding transforming growth factor (TGF)-ß, α-smooth muscle actin (SMA), type IV collagen, and fibronectin were elevated at 3 days after GFS. IL-6 trans-signaling and OSM signaling suppressed TGF-ß-induced expression of α-SMA and collagen IV, as well as activation of the non-canonical TGF-ß pathway, suggesting that IL-6 and OSM may aid in controlling the phase transition from inflammation to proliferation and remodeling. The suppressive effects of OSM were accompanied by STAT3 activation, such that STAT1 function was complementary to STAT3. Taken together, these observations indicated that IL-6 family members constitute early response genes after GFS, which can suppress TGF-ß-induced expression of late response genes at the surgical site after GFS.
Subject(s)
Ciliary Neurotrophic Factor/metabolism , Conjunctiva/pathology , Interleukin-6/metabolism , Leukemia Inhibitory Factor/metabolism , Oncostatin M/metabolism , Wound Healing/physiology , Actins/metabolism , Animals , Blotting, Western , Collagen Type IV/metabolism , Conjunctiva/metabolism , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibrosis , Glaucoma/surgery , Humans , Rabbits , Real-Time Polymerase Chain Reaction , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , Trabeculectomy , Transforming Growth Factor beta/pharmacologyABSTRACT
Transforming growth factor-beta 2 (TGF-ß2) is highly concentrated in the aqueous humor of primary open-angle glaucoma patients. TGF-ß2 causes fibrosis of outflow tissues, such as the trabecular meshwork (TM), and increases intraocular pressure by increasing resistance to aqueous humor outflow. Recently, histone deacetylase (HDAC) activity was investigated in fibrosis in various tissues, revealing that HDAC inhibitors suppress tissue fibrosis. However, the effect of HDAC inhibitors on fibrosis in the eye was not determined. Here, we investigated the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on TGF-ß2-induced increased resistance to aqueous humor outflow. We found that SAHA suppressed TGF-ß2-induced outflow resistance in perfused porcine eyes. Moreover, SAHA cotreatment suppressed TGF-ß2-induced ocular hypertension in rabbits. The permeability of monkey TM (MTM) and Schlemm's canal (MSC) cell monolayers was decreased by TGF-ß2 treatment. SAHA inhibited the effects of TGF-ß2 on the permeability of these cells. TGF-ß2 also increased the expression of extracellular matrix proteins (fibronectin and collagen type I or IV) in MTM, MSC, and human TM (HTM) cells, while SAHA inhibited TGF-ß2-induced extracellular matrix protein expression in these cells. SAHA also inhibited TGF-ß2-induced phosphorylation of Akt and ERK, but did not inhibit Smad2/3 phosphorylation, the canonical pathway of TGF-ß signaling. Moreover, SAHA induced the expression of phosphatase and tensin homolog, a PI3K/Akt signaling factor, as well as bone morphogenetic protein 7, an endogenous antagonist of TGF-ß. These results imply that SAHA prevents TGF-ß2-induced increases in outflow resistance and regulates the non-Smad pathway of TGF-ß signaling in TM and MSC cells.
Subject(s)
Transforming Growth Factor beta2/metabolism , Vorinostat/metabolism , Vorinostat/pharmacology , Animals , Aqueous Humor/metabolism , Aqueous Humor/physiology , Collagen Type I/metabolism , Extracellular Matrix/metabolism , Extracellular Matrix Proteins/metabolism , Fibronectins/metabolism , Glaucoma, Open-Angle/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Macaca fascicularis , Male , Ocular Hypertension/metabolism , Phosphorylation , Primary Cell Culture , Rabbits , Signal Transduction , Swine , Trabecular Meshwork/drug effects , Transforming Growth Factor beta2/physiology , Transforming Growth Factors/metabolismABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0242626.].
ABSTRACT
Increasing demand for clinical retinal degeneration therapies featuring human ESC/iPSC-derived retinal tissue and cells warrants proof-of-concept studies. Here, we established two mouse models of end-stage retinal degeneration with immunodeficiency, NOG-rd1-2J and NOG-rd10, and characterized disease progress and immunodeficient status. We also transplanted human ESC-derived retinal sheets into NOG-rd1-2J and confirmed their long-term survival and maturation of the structured graft photoreceptor layer, without rejection or tumorigenesis. We recorded light responses from the host ganglion cells using a multi-electrode array system; this result was consistent with whole-mount immunostaining suggestive of host-graft synapse formation at the responding sites. This study demonstrates an application of our mouse models and provides a proof of concept for the clinical use of human ESC-derived retinal sheets.
Subject(s)
Embryonic Stem Cells/pathology , Retina/pathology , Retinal Degeneration/pathology , Animals , Disease Models, Animal , Female , Humans , Induced Pluripotent Stem Cells/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Transgenic , Photoreceptor Cells/pathology , Stem Cell Transplantation/methodsABSTRACT
PURPOSE: The purpose of this study was to examine the efficacy and safety of valproic acid (VPA) use in patients with retinitis pigmentosa (RP). PATIENTS AND METHODS: This was a prospective, interventional, noncomparative case study. In total, 29 eyes from 29 patients with RP whose best-corrected visual acuities (BCVAs) in logarithm of the minimum angle of resolution (logMAR) ranged from 1.0 to 0.16 with visual fields (VFs) of ≤10° (measured using Goldmann perimeter with I4) were recruited. The patients received oral supplementation with 400 mg of VPA daily for 6 months and were followed for an additional 6 months. BCVAs, VFs (measured with the Humphrey field analyzer central 10-2 program), and subjective questionnaires were examined before, during, and after the cessation of VPA supplementation. RESULTS: The changes in BCVA and VF showed statistically significant differences during the internal use of VPA, compared with after cessation (P=0.001). With VPA intake, BCVA in logMAR significantly improved from baseline to 6 months (P=0.006). The mean deviation value of the VF significantly improved from baseline to 1 month (P=0.001), 3 months (P=0.004), and 6 months (P=0.004). These efficacies, however, were reversed to the baseline levels after the cessation of VPA intake. There were no significant relations between the mean blood VPA concentrations of each patient and the changes in BCVA and VF. During the internal use of VPA, 15 of 29 patients answered "easier to see", whereas blurred vision was registered in 21 of 29 patients on cessation. No systemic drug-related adverse events were observed. CONCLUSION: While in use, oral intake of VPA indicated a short-term benefit to patients with RP. It is necessary to examine the effect of a longer VPA supplementation in a controlled study design.