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Scientific Reports 6: Article number: 33830; published online: 22 September 2016; updated: 19 January 2017. This Article contains an error in panel C of Figure 4, where “WT” was incorrectly written as “E50K−tg”. The correct Figure 4 appears below as Figure 1.

Mutations in optineurin (OPTN) are linked to the pathology of primary open angle glaucoma (POAG) and amyotrophic lateral sclerosis. Emerging evidence indicates that OPTN mutation is involved in accumulation of damaged mitochondria and defective mitophagy. Nevertheless, the role played by an OPTN E50K mutation in the pathogenic mitochondrial mechanism that underlies retinal ganglion cell (RGC) degeneration in POAG remains unknown. We show here that E50K expression induces mitochondrial fission-mediated mitochondrial degradation and mitophagy in the axons of the glial lamina of aged E50K-tg mice in vivo. While E50K activates the Bax pathway and oxidative stress, and triggers dynamics alteration-mediated mitochondrial degradation and mitophagy in RGC somas in vitro, it does not affect transport dynamics and fission of mitochondria in RGC axons in vitro. These results strongly suggest that E50K is associated with mitochondrial dysfunction in RGC degeneration in synergy with environmental factors such as aging and/or oxidative stress.

During human embryogenesis, neural crest cells migrate to the anterior chamber of the eye and then differentiate into the inner layers of the cornea, the iridocorneal angle, and the anterior portion of the iris. When proper development does not occur, this causes iridocorneal angle dysgenesis and intraocular pressure (IOP) elevation, which ultimately results in developmental glaucoma. Here, we show that heparan sulfate (HS) deficiency in mouse neural crest cells causes anterior chamber dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal angle dysgenesis. These dysfunctions are phenotypes of the human developmental glaucoma, Peters anomaly. In the neural crest cells of mice embryos, disruption of the gene encoding exostosin 1 (Ext1), which is an indispensable enzyme for HS synthesis, resulted in disturbed TGF-[[beta].sub.2] signaling. This led to reduced phosphorylation of Smad2 and downregulated expression of forkhead box C1 (Foxc1) and paired-like homeodomain transcription factor 2 (Pitx2), transcription factors that have been identified as the causative genes for developmental glaucoma. Furthermore, impaired interactions between HS and TGF-[[beta].sub.2] induced developmental glaucoma, which was manifested as an IOP elevation caused by iridocorneal angle dysgenesis. These findings suggest that HS is necessary for neural crest cells to form the anterior chamber via TGF-[[beta].sub.2] signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma., Introduction Developmental glaucoma is a congenital blinding disease associated with elevated intraocular pressure (IOP) because of anomalies of the drainage structure for the aqueous humor in the eye. The major [...]

Purpose: To report the occurrence probability of disc haemorrhage (DH) and risk factors for it in otherwise healthy Japanese normal‐tension glaucoma (NTG) patients who had lower normal intraocular pressure (IOP) and were followed without treatment for 5 years. Methods: A prospective observational study. Normal‐tension glaucoma (NTG) patients with IOP consistently ≤15 mmHg without treatment were enrolled. The presence or absence of DH was checked semi‐annually on the fundus photographs by three independent observers, while patients were followed without treatment. Cox proportional hazards model taking inter‐eye correlation into consideration was adopted to identify risk factors for DH occurrence. The main outcomes were DH occurrence probability during 5‐year period and its risk factors. Results: One hundred seventeen eyes of 90 patients with mean age of 54.1 years, mean deviation value of −3.6 decibels and mean IOP during follow‐up of 12.4 mmHg were included. Disc haemorrhage (DH) was observed at least once in 34 eyes and more than twice in 15 eyes during the follow‐up. The DH occurrence probability at 5 years was 31% (95% confidence interval: 21–40%), and lower myopic refraction (HR = 1.18; p = 0.018), higher IOP during follow‐up (HR = 1.35; p = 0.047) and presence of DH at baseline (HR = 4.19; p = 0.002) were its risk factors. Conclusion: Disc haemorrhage (DH) occurrence probability of Japanese healthy NTG patients with mean IOP of 12.4 mmHg and no systemic and/or topical treatment was 31% at 5 years. Lower myopic refraction, higher IOP and its existence at baseline were its risk factors. [ABSTRACT FROM AUTHOR]

Purpose: Axonal transport is fundamental to autophagy in neuronal cells. To understand its biological significance in various conditions, it is necessary to monitor the process of autophagy. However, monitoring methods are often limited to static analyses, such as protein expression and histological observations. Autophagy has multistep process and is highly dynamic; therefore, additional techniques are necessary to study autophagy. In this study, we quantified the dynamics of autophagy-related organelle transport under conditions of dynamic instability and catastrophic disruption of microtubules usingin vitrolive imaging. Materials and methods: Retinal ganglion cells (RGCs) were isolated from postnatal day 3 Sprague–Dawley rats by immunopanning. After 7 days of culture, acidic organelles were stained by LysoTracker. Dynamics of acidic organelles was quantified using kymographs. Colchicine was used to induce microtubule disruption. Movement of acidic organelles was observed at five time points: before, and at 6, 24, 72, and 120 h after colchicine stimulation. Ethidium homodimer-1 (EthD-1) was used to determine cell viability. Results: The status of axonal transport of acidic organelles (n = 363) from 27 RGCs was classified into four categories: anterograde (1.4%), retrograde (90%), stationary (8.0%), and fluttering (0.28%). Six hours after the induction of microtubule disruption in 14 of 27 RGCs, almost all acidic organelles (n = 236) were stationary. All acidic components had completely stopped moving 24 h later. At 72 h after stimulation, axonal fragmentation, and shrinking and disappearance of soma were observed in 71% of RGCs. Finally, the remaining RGCs became positive for EthD-1. In the control (13 of 27 RGCs), axonal transport was maintained for 120 h and EthD-1-positive RGCs were not observed. Conclusion: Almost all acidic organelles were transported retrogradely along the axon, which was inhibited by colchicine. Understanding the dynamics of acidic organelles may provide useful parameters for characterizing autophagy of neuronal cells in pathophysiological conditions. [ABSTRACT FROM PUBLISHER]