ASK has been identified as an ASK binding protein Wang
ASK2 has been identified as an ASK1 binding protein (Wang et al., 1998). ASK1 supports the stability and active configuration of ASK2 in the heteromeric complex, while ASK2 has been found to activate ASK1 by direct phosphorylation (Takeda et al., 2007). Unlike ASK1, which is ubiquitously expressed in various tissues, ASK2 is specifically expressed in tissues such as those of the skin, lungs, and gastrointestinal tract (Iriyama et al., 2009). A novel function of ASK2 in skin tumorigenesis has been elucidated along with the complex relationship between ASK2 and ASK1 (Iriyama et al., 2009). ASK2 eliminates damaged Fmoc-Ser-OH receptor through apoptosis and functions as a tumor suppressor in the initial stage, whereas ASK1 functions as a tumor promoter by inducing inflammation (Iriyama et al., 2009).
Finally, the last member of the ASK family, ASK3, is predominantly expressed in the kidneys. ASK3 is a unique bidirectional responder to osmotic stress, having a role in the control of blood pressure (Naguro et al., 2012).
ASK1 is the only member of the ASK family that has been shown to play a role in NDDs. Here, we review experimental evidence that links ASK1 signaling with the pathogenesis of several NDDs (Table 1). We propose that ASK1 may be a new point of therapeutic intervention to prevent or treat NDDs.
ASK1 in glaucoma Glaucoma is an NDD of the eye and is one of the leading causes of vision loss in the world. It is estimated that glaucoma will affect more than 80 million individuals worldwide by 2020, with at least 6.8 million individuals becoming bilaterally blind (Quigley and Broman, 2006). Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons. The factors associated with the pathogenesis of glaucoma include high intraocular pressure (IOP), increased oxidative stress, aging, glutamate neurotoxicity, endoplasmic reticulum (ER) stress, and mutations in susceptibility genes such as optineurin and myocilin (Anholt and Carbone, 2013, Janssen et al., 2013, Kimura et al., 2017, Osborne and del Olmo-Aguado, 2013, Seki and Lipton, 2008). Among these factors, oxidative stress is an important risk factor in human glaucoma (Goyal et al., 2014, Kimura et al., 2017), and the plasma level of glutathione (GSH), an important antioxidant, is consistently decreased in glaucoma patients (Gherghel et al., 2005, Gherghel et al., 2013). A subset of glaucoma termed normal tension glaucoma (NTG) presents with statistically normal IOP, and there is an unexpectedly high prevalence of NTG in Japan and other Asian countries (Iwase et al., 2004, Kim et al., 2011). We previously reported that the loss of one of the glutamate transporters EAAC1 and GLAST leads to RGC degeneration in mice, which then exhibit the key pathological features of NTG as a result of increased glutamate neurotoxicity and oxidative stress (Harada et al., 2007). Indeed, the expression of 4-hydroxy-2-nonenal (4-HNE), which represents oxidative stress levels, has been shown to be upregulated in the retina of EAAC1 KO mice (Guo et al., 2016, Noro et al., 2015) and GLAST KO mice (Kimura et al., 2015), suggesting that oxidative stress is involved in the pathogenesis of glaucoma. Although currently available glaucoma therapy focuses on the reduction of IOP, some patients do not respond to this type of treatment, and research into the neuroprotection of RGCs as a novel therapeutic strategy is advancing. We have been using the animal models discussed above to examine new potential therapeutic targets for glaucoma (Guo et al., 2016, Harada et al., 2010, Kimura et al., 2015, Noro et al., 2015, Semba et al., 2014a, Semba et al., 2014b). One such strategy is the reduction of oxidative stress or ER stress (Kimura et al., 2017, Nakano et al., 2016, Osborne and del Olmo-Aguado, 2013). Moreover, ASK1 gene deletion prevents RGC death in various mouse models of glaucoma (Harada et al., 2006, Harada et al., 2010, Katome et al., 2013). We reported that ASK1 KO mice were less susceptible to retinal ischemic injury (Harada et al., 2006) and that the number of surviving retinal neurons in ASK1 KO mice was significantly increased, while the numbers of cleaved-caspase-3- and TdT-mediated dUTP nick end labeling (TUNEL)-positive neurons were decreased compared with those in wild-type mice (Harada et al., 2006). In ASK1 KO mice with optic nerve injury, p38 activation and RGC loss were suppressed (Katome et al., 2013). Sequential in vivo retinal imaging revealed that treatment of the eyeball with a p38 inhibitor effectively protected RGCs even after optic nerve injury (Katome et al., 2013). Furthermore, ASK1 deficiency also protected RGCs and decreased the number of degenerating axons in the optic nerves of GLAST KO mice (GLAST and ASK1 double KO mice) (Harada et al., 2010). Consistent with this finding, visual function was significantly improved in the double KO mice (Harada et al., 2010). Taken together, in all the models we have used, ASK1 deficiency led to increased RGC survival, indicating that targeting ASK1 is an effective approach for the treatment of glaucoma. It is important to note that the therapeutic effect of ASK1 deletion may also involve the reduction of factors causing oxidative stress, such as TNF-α (Guo et al., 2010, Osaka et al., 2007), which mediates neurodegeneration in glaucoma (Tezel, 2008). In addition, recent studies have demonstrated the association of TLR4 gene polymorphisms with glaucoma in Japanese, Chinese, and Mexican subjects (Chen et al., 2012, Navarro-Partida et al., 2016, Shibuya et al., 2008, Takano et al., 2012). For example, in the NTG groups, the allele frequency of rs2149356 of the TLR4 gene was the most significantly different from that of the control group (Takano et al., 2012). Because ASK1 mediates TLR4 signaling (Guo et al., 2010, Matsuzawa et al., 2005), the association of TLR4 gene polymorphisms with glaucoma further indicates the involvement of ASK1 with glaucoma. Currently, we are examining whether a therapeutic effect is achieved by the oral administration of an ASK1 inhibitor in GLAST KO mice to further confirm that ASK1 inhibition is a promising target for glaucoma treatment.