ASK1 in neurodegeneration

Advances in Biological Regulation xxx (2017) 1e9

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ASK1 in neurodegeneration Xiaoli Guo*, Kazuhiko Namekata, Atsuko Kimura, Chikako Harada, Takayuki Harada Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 25 July 2017 Received in revised form 28 August 2017 Accepted 29 August 2017 Available online xxx

Neurodegenerative diseases (NDDs) such as glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are characterized by the progressive loss of neurons, causing irreversible damage to patients. Longer lifespans may be leading to an increase in the number of people affected by NDDs worldwide. Among the pathways strongly impacting the pathogenesis of NDDs, oxidative stress, a condition that occurs because of an imbalance in oxidant and antioxidant levels, has been known to play a vital role in the pathophysiology of NDDs. One of the molecules activated by oxidative stress is apoptosis signal-regulating kinase 1 (ASK1), which has been shown to play a role in NDDs. ASK1 activation is regulated by multiple steps, including oligomerization, phosphorylation, and protein-protein interactions. In the oxidative stress state, reactive oxygen species (ROS) induce the dissociation of thioredoxin, a protein regulating cellular reduction and oxidation (redox), from the N-terminal region of ASK1, and ASK1 is subsequently activated by the oligomerization and phosphorylation of a critical threonine residue, leading to cell death. Here, we review experimental evidence that links ASK1 signaling with the pathogenesis of several NDDs. We propose that ASK1 may be a new point of therapeutic intervention to prevent or treat NDDs. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ASK1 in glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ASK1 in multiple sclerosis and optic neuritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ASK1 in Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ASK1 in Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ASK1 in amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ASK1 in Huntington's disease and other polyglutamine diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ASK1 in other neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. Visual Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. E-mail address: [email protected] (X. Guo). http://dx.doi.org/10.1016/j.jbior.2017.08.003 2212-4926/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Guo, X., et al., ASK1 in neurodegeneration, Advances in Biological Regulation (2017), http:// dx.doi.org/10.1016/j.jbior.2017.08.003

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Neurodegenerative diseases (NDDs) are characterized by the progressive dysfunction and loss of neurons affecting distinct functional systems, which define their clinical presentations. There are many types of NDDs, such as glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). All forms of NDDs have a massive impact on the patients, affecting not only quality of life but also lifespan. The major threats posed by NDDs include progressive loss of vision (glaucoma) and memory (AD), impairments in movement (MS and PD), and the inability to walk, talk, or think (ALS and HD). While medications for these diseases are available, the existing medicines only treat the symptoms (Manoharan et al., 2016). Many pathways, including misfolded proteins and protein elimination pathways such as the ubiquitin-proteasome system and the autophagy-lysosome pathway (Nijholt et al., 2011; Tanaka and Matsuda, 2014), stress response proteins, and chaperones have a high impact on the pathogenesis of NDDs. The intimate relationship among microglial activation, nitric oxide, and neuroinflammation in the human brain is also widely discussed in relation to NDDs (Yuste et al., 2015). In addition, oxidative stress and the formation of free radicals or reactive oxygen species (ROS), mitochondrial dysfunctions, impaired bioenergetics, DNA damage, and the disruption of cellular or axonal transport are linked to the formation of toxic forms of NDD-related proteins (Jellinger, 2010). Among these, oxidative stress, a condition resulting from an imbalance in oxidant and antioxidant levels, has been known to play a vital role in the pathophysiology of NDDs including glaucoma, MS, AD, PD, ALS, and HD. Many studies have utilized oxidative stress biomarkers to investigate the severity of these NDDs. The apoptosis signal-regulating kinase (ASK) family is a family of mitogen-activated protein kinase (MAPK) kinase kinases with three members, ASK1, ASK2, and ASK3. Accumulating evidence indicates that ASK1 plays a key role in the pathogenesis of NDDs such as glaucoma, MS, HD, and AD (Hayakawa et al., 2012; Sekine et al., 2006). ASK1 activation is regulated by multiple steps including oligomerization, phosphorylation, and protein-protein interactions (Chen et al., 2008; Hwang et al., 2005; Lau et al., 2007; Matsuzawa et al., 2002; Zhang et al., 1999). Thioredoxin (Trx), which regulates cellular reduction and oxidation (redox), is bound directly to the N-terminal region of ASK1 (Nishitoh et al., 2002). In the oxidative stress state, reactive oxygen species induce the dissociation of Trx from ASK1, and ASK1 is subsequently activated by the oligomerization and phosphorylation of a critical threonine residue (Gotoh and Cooper, 1998; Nishitoh et al., 2002). Moreover, ASK1 can mediate Toll-like receptor 4 (TLR4) signaling to p38 through a ROS-dependent pathway (Guo et al., 2010; Matsuzawa et al., 2005). Therefore, ASK1 is one of the key mediators of oxidative stress. 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

Table 1 Summary of ASK1-related neurodegenerative diseases. Disease

Symptoms

Affected cell types

References

Glaucoma Multiple sclerosis

Progressive loss of vision Impairments in the movement; loss of vision Loss of memory

Retinal ganglion cells Oligodendrocytes; neurons

Harada et al., 2006, 2010 Guo et al., 2010

Neurons in the hippocampus and cortex Neurons in the substantia nigra

Kadowaki et al., 2005; Peel et al., 2004

Motor neurons

Fujisawa et al., 2016; Nishitoh et al., 2008

Inability to walk, talk, and think

Striatal and cortical neurons

Hippocampal sclerosis

Neurons in the hippocampus and cortex Oligodendrocytes; neurons

Arning et al., 2008; Cho et al., 2009; Minn et al., 2008; Nishitoh et al., 2002 Liu et al., 2011

Alzheimer's disease Parkinson's disease Amyotrophic lateral sclerosis Huntington's disease Mesial temporal lobe epilepsy Progressive cervical cord compression

Movement disorder (rigidity, resting tremor, bradylinesia) Progressive muscle weakness

Spinal cord dysfunction

Hu et al., 2011; Lee et al., 2012

Takenouchi et al., 2008

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damaged cells 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. 2. 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 OlmoAguado, 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, 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, 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, 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-a (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. 3. ASK1 in multiple sclerosis and optic neuritis Multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), is the most common neurological disease among young adults in the United States and Europe (Dutta and Trapp, 2011). Although MS primarily affects myelin, axonal degeneration and neuron loss frequently occur early in the course of the disease. While the functional consequences of inflammation and demyelination are at least in part reversible, the deficit due to axonal loss is irreversible, leading to permanent disability (Bjartmar et al., 2000, 2003; Kornek and Lassmann, 1999). Therapeutic strategies to prevent axonal and neuronal degeneration are thus urgently warranted. Moreover, it is likely that neuroprotective strategies that directly target neurons may complement immunomodulatory interventions that act on immune cells and molecules, so that the two therapeutic approaches can be used in combination. Please cite this article in press as: Guo, X., et al., ASK1 in neurodegeneration, Advances in Biological Regulation (2017), http:// dx.doi.org/10.1016/j.jbior.2017.08.003

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Optic neuritis is a demyelinating inflammation of the optic nerve that typically affects adults ranging from 18 to 45 years old. There is a strong association between optic neuritis and MS, in which optic neuritis is the initial presentation of MS for approximately 20% of MS patients and the risk of developing MS within 15 years after the onset of optic neuritis is approximately 50% (Optic Neuritis Study Group, 2008). Research into optic neuritis is somewhat limited compared with MS research, but it is an important area of investigation that is seeing continuous progress. In preclinical studies, experimental autoimmune encephalomyelitis (EAE), an animal model of MS, is often used to study optic neuritis. Accumulating data indicate that oxidative stress plays a major role in the pathogenesis of MS, optic neuritis, and EAE (Gilgun-Sherki et al., 2004). Indeed, a drastic rise in hydrogen peroxide (H2O2) levels, which was detected by the probe 20 ,70 -dichlorofluorescein diacetate (DCFDA), was found in the optic nerves of EAE mice on day six after MOG immunization (Guo et al., 2011). Many studies demonstrate that antioxidants such as lipoic acid, spermidine, and geranylgeranylacetone (GGA) are effective in suppressing inflammation in the spinal cord and optic nerve (Chaudhary et al., 2011; Guo et al., 2009, 2011). Furthermore, gene therapy with antioxidant genes, namely SOD2 and catalase, was effective in reducing optic nerve demyelination, axonal loss, and RGC loss in EAE mice (Qi et al., 2007a, 2007b). These findings suggest that oxidative stress is associated with the pathogenesis of MS and optic neuritis and is an effective target for their treatment. We previously reported that ASK1 deficiency in T cells has no effect on their proliferation, indicating that ASK1 in immune cells has no effect on the severity of MS or optic neuritis (Guo et al., 2010). However, in addition to immune cells, CNS resident glial cells play important roles in demyelinating neuroinflammation (Brosnan and Raine, 2013; Horstmann et al., 2013). Indeed, the ASK1-p38 pathway in astrocytes and microglia plays an essential role in the release of key cytokines during neuroinflammation, including monocyte chemoattractant protein-1 (MCP-1); macrophage inflammatory protein-1 alpha (MIP-1a); regulated on activation, normal T cell expressed and secreted (RANTES); and TNF-a (Guo et al., 2010). In conventional ASK1 KO EAE mice, the reduction of such proinflammatory cytokines as well as a decrease in the upregulation of inducible nitric oxide synthase (iNOS) leads to the suppression of neuroinflammation and of demyelination of the spinal cord and optic nerve. EAE causes a reduction in visual function, which can be assessed by electroretinogram, but ASK1 deficiency ameliorates this visual impairment (Guo et al., 2010), indicating that the inhibition of ASK1 is effective both histologically and functionally. These findings, in combination with in vitro data from primary cultured microglia and astrocytes, suggest that the ASK1 signaling pathway in microglia and astrocytes plays a role in the degeneration of the spinal cord and optic nerve in this model (Guo et al., 2010). Currently, we are examining the roles of ASK1 in various cell types during EAE using cell-typespecific ASK1 KO mice. Because ASK1 signaling in microglia and astrocytes is important during EAE, we hypothesized that a combination therapy that targets T cells along with microglia and astrocytes would further ameliorate the severity of EAE. We tested this hypothesis by applying valproic acid (VPA)da short-chain fatty acid, widely prescribed as an antiepileptic drug, that suppresses the activation of T cells (Lv et al., 2012)dto ASK1 KO EAE mice. We found that VPA and ASK1 inhibition have synergistic therapeutic effects on EAE (Azuchi et al., 2017). In addition, we demonstrated that the oral administration of an ASK1 inhibitor, MSC2032964A, is effective in suppressing neuroinflammation and demyelination in EAE mice (Guo et al., 2010). These results suggest that the inhibition of ASK1 is a promising strategy for the treatment of MS. To elucidate the clinical relevance of ASK1 in MS, we are examining the activation of ASK1 in the brains of MS patients. 4. ASK1 in Alzheimer's disease Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects memory, language, and thought. As the most common neurodegenerative disorder, AD has risen in prevalence to an estimated 40 million patients worldwide, but the true number is undoubtedly much higher, as it is known that the disease begins in the brain at least two to three decades before one first experiences memory loss (Selkoe and Hardy, 2016). AD may begin with an imbalance between the production and clearance of the self-aggregating amyloid b protein (Ab) in the hippocampus or cortex, both of which serve memory and cognition (Selkoe, 2013). Ab is generated by the sequential cleavage of the amyloid precursor protein (APP) by two intramembrane proteases, b- and g-secretase. Under normal physiological conditions, Ab40 is mainly generated, whereas under pathological conditions, Ab42, the toxic form of Ab, is produced and intracellularly accumulated. Mutations of the substrate APP and the proteases presenilin 1 and 2 have been suggested to be involved in this process (Selkoe, 2013). ROS production and the activation of c-Jun N-terminal kinases (JNKs) are involved in many pathological mechanisms of AD (Ebenezer et al., 2010). Accumulating evidence indicates that ASK1 plays a key role in the pathogenesis of AD. Ab leading to AD pathology (Jucker and Walker, 2011) can activate ASK1, which is required for ROSand ER-stress-induced JNK activation (Imaizumi et al., 2001; Kadowaki et al., 2005; Nakagawa et al., 2000; Nishitoh et al., 2002). The activation of ASK1 also leads to tau phosphorylation, which aggravates AD pathology (Peel et al., 2004). Moreover, ASK1 is associated with insulin signal transduction, the dysfunction of which in the brain leads to cognitive decline (Cholerton et al., 2013). Insulin-like growth factor-1 receptor (IGF-1R) signaling can suppress apoptosis, interfere downstream of tumor necrosis factor receptor (TNF-R) activation, and block the ASK1-mediated activation of the JNK/p38 pathway (Hueber et al., 1997). Immunotherapeutic agents are undergoing the most study as a therapeutic strategy for treating AD. However, other antiamyloid strategies and therapies aimed at the downstream processes of the disease are of great interest. The inhibition of ASK1 induces tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and prevents cognitive decline in the brain. Even though activation of ASK1 has not yet been reported in the AD brain, previous studies have indirectly demonstrated that Please cite this article in press as: Guo, X., et al., ASK1 in neurodegeneration, Advances in Biological Regulation (2017), http:// dx.doi.org/10.1016/j.jbior.2017.08.003

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levels of glutaredoxin-1 and Trx, antioxidants that can inhibit ASK1, are decreased in the AD brain (Akterin et al., 2006). Hence, the inhibition of ASK1 may be an effective approach to preventing or reducing the risk of Alzheimer's disease (Selkoe and Hardy, 2016). 5. ASK1 in Parkinson's disease Parkinson's disease (PD) is the second-most-common neurodegenerative disorder after Alzheimer's disease, affecting 2e3% of the worldwide population 65 or older. As a movement disorder, PD is characterized by rigidity, resting tremors, and bradykinesia (Rodriguez-Oroz et al., 2009). The neuropathological hallmarks of PD include neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of a-synuclein. Its underlying molecular pathogenesis involves multiple pathways and mechanisms: a-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation (Poewe et al., 2017). No therapies are yet available to prevent the loss of midbrain dopaminergic (mDA) neurons or even delay the course of the disease (Brichta et al., 2013). Conventional pharmacological treatments for PD are dopamine precursors (levodopa, L-DOPA, L-3,4dihydroxyphenylalanine) and other symptomatic treatments, including dopamine agonists (amantadine, etc.), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). These pharmacological treatments can induce side effects such as psychomotor and autonomic complications. In addition, patients may feel that improvement from the chronic administration of these drugs gradually fades and that they need to take doses with increasing frequency. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration and enhance dopaminergic neurotransmission (Cacabelos, 2017). PD research involves the use of many animal models, which can be categorized into two main types: toxic modelsdamong which the two most widely used are the classical 6-hydroxydopamine (6-OHDA) model in rats and the 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in mice and monkeysdand genetic models such as the asynuclein model in transgenic mice and the PTEN-induced putative kinase 1 (PINK1) KO model in mice (Blesa and Przedborski, 2014; Koyano et al., 2014). To exert its toxicity in vivo, MPTP is first converted to MPPþ, and ASK1 in dopamine neurons relays the signals originating from MPPþ to produce the molecules responsible for glial activation, such as cyclooxygenase-2. ASK1 activation in the substantia nigra has been reported in wild-type mice with systemic exposure to MPTP (Lee et al., 2012), and dopaminergic neuronal loss in ASK1 KO mice was dampened along with reduced inflammatory indicators and less pronounced motor impairment. This suggests that ASK1 signaling plays an important role as a link between oxidative stress and neuroinflammation in MPTP-induced toxicity in mice (Lee et al., 2012). Moreover, a similar trend of diminished 6-OHDA toxicity was found in the mouse nigra with shRNA mediated ASK1 knockdown (Hu et al., 2011). It will be interesting to investigate whether the pharmacological inhibition of ASK1 improves PD symptoms. 6. ASK1 in amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects the motor neurons in the motor cortex, brainstem, and spinal cord, resulting in progressive muscle weakness (Rowland and Shneider, 2001). In the Western world, ALS has an incidence rate of 1e2 individuals per 100,000 per year and a prevalence of 4e8 individuals per 100,000 (Logroscino et al., 2010). In approximately 10% of ALS patients, the disease runs in the family (familial ALS, FALS), and approximately 90% are classified as having sporadic ALS. One gene responsible for 2% of ALS cases is Cu/Zn-superoxide dismutase 1 (SOD1) whose mutation specifically causes motor neuron death (Wijesekera and Leigh, 2009). In addition, studies on other causative genes, such as TDP-43 and FUS that can induce the misfolding and/or aggregate formation of SOD1WT, have provided new insights into the pathogenesis of ALS, suggesting that ALS cannot be explained solely by the SOD1 mutation (Hayashi et al., 2016). Moreover, several factors including excitotoxicity, oxidative stress and ER stress have been proposed to be involved in the neurotoxicity associated with mutant SOD1 species (Hayashi et al., 2016). In FALS model mice expressing the ALS-linked SOD1 mutant (SOD1(mut)), activation of ASK1 and p38, which is concomitant with motor neuron death, was revealed by immunohistochemical analysis (Holasek et al., 2005; Veglianese et al., 2006; Wengenack et al., 2004). In elucidating the mechanism how SOD1(mut) activates ASK1, Nishitoh et al. reported an interaction of SOD1(mut) with the putative ER translocon degradation in endoplasmic reticulum protein 1 (Derlin-1) (Nishitoh et al., 2008), which they hypothesized might induce ER stress and ASK1 activation, resulting in cell death (Nishitoh et al., 2008). They confirmed the hypothesis by showing that a polypeptide of the cytosolic region of Derlin-1, which disrupts the SOD1(mut)-Derlin-1 interaction, inhibited SOD1(mut)-induced cell death (Nishitoh et al., 2008). Moreover, motor neuron loss was attenuated in ASK1-deficient FALS model mice, leading to longer lifespans (Nishitoh et al., 2008). In addition, the oral administration of K811 or K812, selective inhibitors of ASK1, significantly extend the lifespans of SOD1(G93A) transgenic mice (Fujisawa et al., 2016). Activation of the p38 cascade was found in the spinal motor neurons of mouse models of FALS, and SOD1(mut)-induced motor neuron degeneration was reduced by the p38 inhibitor semapimod (Dewil et al., 2007; Veglianese et al., 2006). Hence, the ASK1-p38 pathway could be a promising target for the treatment of ALS. Please cite this article in press as: Guo, X., et al., ASK1 in neurodegeneration, Advances in Biological Regulation (2017), http:// dx.doi.org/10.1016/j.jbior.2017.08.003

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Fig. 1. Summary of ASK1 activation, which promotes cell death, in various neurodegenerative disease. ER: endoplasmic reticulum; MPTP: 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine; SOD1: Cu/Zn-superoxide dismutase 1.

7. ASK1 in Huntington's disease and other polyglutamine diseases The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding regions of specific genes, leading to the production of pathogenic proteins containing critically expanded tracts of glutamines. To date, a total of nine polyQ disorders have been described: spinocerebellar ataxias (SCA) types 1, 2, 6, 7, and 17; Machado-Joseph disease (MJD/SCA3); Huntington's disease (HD); dentatorubral-pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). These nine diseases are irreversibly progressive over 10e30 years, severely impairing, and ultimately fatal. In these diseases, pathogenic proteins with expanded polyQ repeats form insoluble aggregates, which disturb the ubiquitin-proteasome system and cause ER stress, resulting in neuronal cell death (Nishitoh et al., 2002). HD, a representative of polyQ diseases, is an autosomal, dominantly inherited disorder. HD is caused by the expansion of polyQ repeats in the N-terminus of the huntingtin (htt) protein and is characterized pathologically by the degeneration of striatal and cortical neurons and the appearance of neuronal inclusions. ASK1 has been shown to be involved in the pathogenesis of polyQ diseases including HD (Nishitoh et al., 2002). In vitro experiments using primary cultured neurons revealed that neuronal cell death caused by JNK activation, which is induced by expanded polyQ repeats and ER stress, was inhibited by ASK1-deficiency (Nishitoh et al., 2002). In addition, increased ASK1 expression and ER stress in the striatum and cortex was found in HD model mice expressing exon 1 of the human HD gene (Cho et al., 2009), and high levels of phosphorylated c-Jun, a major substrate of JNK, have been shown in a rat model of HD (Perrin et al., 2009). These results indicate that ER stress activates the ASK1-JNK pathway in vivo. Consistently, ASK1 inhibition with an anti-ASK1 antibody prevents atrophy of striatal neurons and improves motor function in HD model mice (Cho et al., 2009). Moreover, elevated ASK1 activity was found in an oxidative-stress- and age-dependent manner in mice with HD-like brain lesions that are induced by the injection of the mitochondrial complex II inhibitor 3nitropropionic acid (3-NP) (Minn et al., 2008). Infusion of ASK1 siRNA prevents 3-NP-induced neuronal cell death (Minn et al., 2008). In addition, it was demonstrated using allelic analysis in HD patients that sequence variations of the MAP3K5 and MAP2K6 genes, encoding ASK1 and MKK6 respectively, appear to modify the age of HD onset (Arning et al., 2008). It is also reported that another polyQ protein, ataxin-1 (ATXN1), has an important role in the pathogenesis of SCA1 (Ryu et al., 2010). ATXN1 has been shown to activate the ASK1-JNK pathway, promoting the sumoylation and aggregation of ATXN1, which might lead to neuronal cell death in SCA1 (Ryu et al., 2010). Taken together, these findings suggest an important role of ASK1 in polyQ diseases. 8. ASK1 in other neurodegenerative diseases ASK1 is also reported as playing important roles in other neuronal diseases. Among them, mesial temporal lobe epilepsy (MTLE) is associated with hippocampal sclerosis and is frequently resistant to medications (Cendes et al., 2014). MTLE accounts for almost 80% of all temporal lobe seizures, the most common form of partial or localization-related epilepsy. In the hippocampi of patients with MTLE, the expression of ASK1 and the activation of both JNK and the ER-stress-associated kinase inositol-requiring enzyme 1 (IRE1) are found to be upregulated (Liu et al., 2011). Please cite this article in press as: Guo, X., et al., ASK1 in neurodegeneration, Advances in Biological Regulation (2017), http:// dx.doi.org/10.1016/j.jbior.2017.08.003

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Progressive cervical cord compression, the most common cause of spinal cord dysfunction in people over 55 years old, may occur because of the narrowing of the spinal canal by osteophytes, the loss of axons and oligodendrocytes in the white matter, the loss of neurons in the gray matter (Yu et al., 2009), and the ossification of the posterior longitudinal ligament (OPLL) leading to myelin destruction. Using tiptoe-walking Yoshimura (TWY) mice, a mouse model of progressive cervical cord compression, it has recently been shown that the ASK1-JNK/p38 pathways are activated in both the neurons and oligodendrocytes of compressed spinal cords (Takenouchi et al., 2008). Studies of the genetic or pharmacological manipulation of ASK1 will shed new insights on its roles in these neurodegenerative diseases. 9. Conclusions A large body of evidence indicates that oxidative stress is involved in the pathogenesis of NDDs. Hence, reducing oxidative stress or suppressing its downstream pathways may be beneficial for the treatment of these diseases, especially such chronic diseases as AD or glaucoma. Here we reviewed the involvement of ASK1, a downstream signaling molecule triggered by oxidative stress, in the pathogenesis of various NDDs. ASK1 activation has been reported to be involved in neuronal cell death in these NDDs as well as oligodendritic cell death in MS and progressive cervical cord compression (Fig. 1). While detailed analysis or manipulation of ASK1 in specific cell types is required, ASK1 may be a new point of therapeutic intervention to prevent or treat NDDs. Acknowledgements The authors would like to thank Mayumi Kunitomo, Keiko Okabe, and Sayaka Ihara for their technical assistance. Funding This work was supported by JSPS KAKENHI Grants-in-Aid for Scientific Research (JP16K07076 to X.G., JP16K08635 to K.N., JP17K07123 to A.K., JP16K11308 to C.H., JP15H04999 to T.H.) and the Takeda Science Foundation (T.H.). Conflicts of interest None. References Akterin, S., Cowburn, R.F., Miranda-Vizuete, A., Jimenez, A., Bogdanovic, N., Winblad, B., Cedazo-Minguez, A., 2006. Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer's disease. Cell Death Differ. 13 (9), 1454e1465. Anholt, R.R., Carbone, M.A., 2013. A molecular mechanism for glaucoma: endoplasmic reticulum stress and the unfolded protein response. Trends Mol. Med. 19 (10), 586e593. Arning, L., Monte, D., Hansen, W., Wieczorek, S., Jagiello, P., Akkad, D.A., Andrich, J., Kraus, P.H., Saft, C., Epplen, J.T., 2008. ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. J. Mol. Med. (Berl.) 86 (4), 485e490. 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Please cite this article in press as: Guo, X., et al., ASK1 in neurodegeneration, Advances in Biological Regulation (2017), http:// dx.doi.org/10.1016/j.jbior.2017.08.003