Pro‐apoptotic role of c‐Jun in NMDA‐induced neurotoxicity in the rat retina

Munemasa, Yasunari; Ohtani-Kaneko, Ritsuko; Kitaoka, Yasushi; Kumai, Toshio; Kitaoka, Yuka; Hayashi, Yasuhiko; Watanabe, Minoru; Takeda, Hiroyuki; Hirata, Kazuaki; Ueno, Satoki

doi:10.1002/jnr.20786

Cited by 28 publications

(29 citation statements)

References 48 publications

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“…Protection in these studies has been attributed to a reduction in phosphorylated JUN (pJUN) leading to an attenuation of JUN/AP-1 activity. JUN is known to be upregulated after various axonal and/or glaucoma relevant insults in RGCs (Isenmann and Bahr, 1997; Levkovitch-Verbin et al, 2005; Munemasa et al, 2006). To determine if JNK could be mediating RGC death by a JUN dependent pathway after axonal injury, activation of JUN (as measured by phosphorylation of Ser-63) was assessed in wildtype and Jnk mutant mice after CONC.…”

Section: Resultsmentioning

confidence: 99%

JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death

Fernandes

Harder

Fornarola

et al. 2012

Neurobiology of Disease

126

187

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Glaucoma is a neurodegenerative disease characterized by the apoptotic death of retinal ganglion cells (RGCs). The primary insult to RGCs in glaucoma is thought to occur to their axons as they exit the eye in the optic nerve head. However, pathological signaling pathways that exert central roles in triggering RGC death following axonal injury remain unidentified. It is likely that the first changes to occur following axonal injury are signal relay events that transduce the injury signal from the axon to the cell body. Here we focus on the c-Jun N-terminal kinase (JNK1-3) family, a signaling pathway implicated in axonal injury signaling and neurodegenerative apoptosis, and likely to function as a central node in axonal injury-induced RGC death. We show that JNK signaling is activated immediately after axonal injury in RGC axons at the site of injury. Following its early activation, sustained JNK signaling is observed in axonally-injured RGCs in the form of JUN phosphorylation and upregulation. Using mice lacking specific Jnk isoforms, we show that Jnk2 and Jnk3 are the isoforms activated in injured axons. Combined deficiency of Jnk2 and Jnk3 provides robust long-term protection against axonal injury-induced RGC death and prevents downregulation of the RGC marker, BRN3B, and phosphorylation of JUN. Finally, using Jun deficient mice, we show that JUN-dependent pathways are important for axonal injury-induced RGC death. Together these data demonstrate that JNK signaling is the major early pathway triggering RGC death after axonal injury and may directly link axon injury to transcriptional activity that controls RGC death.

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Section: Resultsmentioning

confidence: 99%

JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death

Fernandes

Harder

Fornarola

et al. 2012

Neurobiology of Disease

126

187

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“…Our previous study showed that axotomy of the optic nerve causes a change in redox status, indicating an increase in Trx1 and Trx2 levels in isolated RGCs. Overexpression of Trx1 and Trx2 prevents axotomy-induced RGC loss, indicating the critical role of the redox status in axotomized RGC degeneration (Munemasa et al, 2006). …”

Section: Cell Body Injurymentioning

confidence: 99%

“…Intracellular Ca 2+ influx also affects mitochondrial activity, such as the release of cytochrome C and ROS, and results in the activation of several apoptotic pathways. Our previous studies on the downstream intracellular Ca 2+ influx led us to propose that the activation of proapoptotic molecules, such as NF-κB p65 and p38, c-Jun N -terminal kinase (JNK), and c-Jun, plays a role in NMDA-induced neurotoxicity (Kitaoka et al, 2004; Munemasa et al, 2005, 2006; Takada et al, 2011). An inflammatory response, i.e., the upregulation of IL-1β, is also observed in the glia and RGCs after NMDA administration, suggesting the involvement of inflammation in response to excitotoxicity.…”

Section: Cell Body Injurymentioning

confidence: 99%

Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection

Munemasa¹,

Kitaoka²

2013

Front. Cell. Neurosci.

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Glaucoma, which affects more than 70 million people worldwide, is a heterogeneous group of disorders with a resultant common denominator; optic neuropathy, eventually leading to irreversible blindness. The clinical manifestations of primary open-angle glaucoma (POAG), the most common subtype of glaucoma, include excavation of the optic disc and progressive loss of visual field. Axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies are observed in glaucoma, in which the reduction of intraocular pressure (IOP) is known to slow progression of the disease. A pattern of localized retinal nerve fiber layer (RNFL) defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. The mechanisms of degeneration of neuronal cell bodies and their axons may differ. In this review, we addressed the molecular mechanisms of cell body death and axonal degeneration in glaucoma and proposed axonal protection in addition to cell body protection. The concept of axonal protection may become a new therapeutic strategy to prevent further axonal degeneration or revive dying axons in patients with preperimetric glaucoma. Further study will be needed to clarify whether the combination therapy of axonal protection and cell body protection will have greater protective effects in early or progressive glaucomatous optic neuropathy (GON).

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“…Immunoblot analysis was carried out as described previously. 49,50 Briefly, 2-5 mg of protein was separated on a 12.5% SDS-polyacrylamide gel and transferred to the polyvinylidene membrane (Millipore, Bedford, MA, USA). After blocking with 5% nonfat milk, the membranes were incubated with primary polyclonal antibodies against Txnip (Zymed Laboratories, San …”

Section: Immunoblot Analysismentioning

confidence: 99%

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

et al. 2008

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We investigated the neuroprotective effect of thioredoxin 1 (Trx1) and thioredoxin 2 (Trx2) which play critical roles in the regulation of oxidative stress on retinal ganglion cells (RGCs) in a rat glaucoma model. Expression of Trx1 and Trx2 and Trx-interacting protein (Txnip) was observed in the RGC layer (GCL), nerve fiber layer and inner nuclear layer. Txnip-, Trx1-and Trx2-expressing cells in the GCL were primarily colocalized with RGCs. The increased Txnip protein level was observed 2 and 5 weeks after glaucoma induction. Trx1 level decreased 2 weeks after glaucoma induction and more prominently after 5 weeks. No change in Trx2 levels was detected. The effects of Trx1 and Trx2 overexpression on RGC survival were evaluated 5 weeks after glaucoma induction. In nontransfected and EGFP-transfected (used as a negative control) retinas, RGC loss was approximately 27% compared with control. The loss of RGCs in Trx1-and Trx2-transfected retinas was approximately 15 and 17%, respectively. Thus, Trx1 and Trx2 preserved 45 and 37% of cells, respectively that were destined to die in glaucomatous retinas. The results of this study provide evidence for the involvement of oxidative stress in RGC degeneration in experimental glaucoma and point to potential strategies to reduce its impact.

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Pro‐apoptotic role of c‐Jun in NMDA‐induced neurotoxicity in the rat retina

Cited by 28 publications

References 48 publications

JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death

JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death

Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection

Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

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