They also have the potential to provide much needed progress in the treatment of chronic pain, opening up new avenues for drug development. This work was supported by the Wellcome Trust. Illustrations by Ken Vail Graphic Design. “
“Retinal ganglion cells (RGCs) are the only neurons that relay visual information from the retina to the brain. These neurons are highly vulnerable when their axons, which collectively form the optic nerve,

Selleck DAPT are damaged (Levin, 1997). For example, traumatic optic nerve injury and subsequent loss of RGCs often occur in the setting of head injury, as a consequence of traffic accidents or falls. In rodents, the majority of RGCs undergo cell death around 2 weeks after intraorbital optic nerve injury (Berkelaar et al., 1994, McKernan and Cotter, 2007 and Sellés-Navarro et al., 2001), creating a first hurdle for successful neural repair. In addition to optic nerve trauma, the retinal pathology of different types of optic neuropathy, in particular glaucoma, is also characterized by selective RGC loss (Howell et al., 2007, Kerrigan et al., 1997, Libby et al., 2005, Quigley, 1993, Quigley et al.,

1995 and Weinreb and Khaw, 2004). In these conditions, RGC loss has been attributed to apoptotic death (Howell et al., 2007, Kerrigan et al., 1997, Libby et al., ABT-737 mouse 2005, Quigley, 1993, Quigley et al., 1995, Weinreb and Khaw, 2004 and Qu et al., 2010). However, RGC apoptosis may occur as the

last step in these diseases, so that targeting apoptotic effectors may not be an efficient strategy for therapy. Thus, deciphering the key upstream signals that trigger the apoptotic cascade in RGCs should provide important targets for therapeutic interventions. Multiple stimuli, such as hypoxia, nutrient deprivation, viral infection, and disturbance of calcium ADAMTS5 levels, can directly or indirectly cause accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), triggering an ER stress condition which leads to an evolutionarily conserved unfolded protein response (UPR) (Ron and Walter, 2007). The UPR has been proposed to be a protective mechanism that limits ER protein loading by inhibiting protein translation, facilitates protein folding through increasing the expression of ER chaperones, and removes misfolded proteins from the ER through degradation. However, prolonged and unrestrained ER stress could lead to the activation of proapoptotic signaling pathways. In mammals, the UPR includes three signal-transduction pathways initiated by three ER-resident stress-sensing proteins: protein kinase RNA-like ER kinase (PERK), inositol-requiring protein-1 (IRE1), and activating transcription factor-6 (ATF6). PERK activation leads to the phosphorylation of the eukaryotic inactivation factor 2α (eIF2α).