Because ASK signaling in microglia and astrocytes is importa

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 (+)-Usniacin (VPA)—a short-chain fatty acid, widely prescribed as an antiepileptic drug, that suppresses the activation of T cells (Lv et al., 2012)—to 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.
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 β protein (Aβ) in the hippocampus or cortex, both of which serve memory and cognition (Selkoe, 2013). Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) by two intramembrane proteases, β- and γ-secretase. Under normal physiological conditions, Aβ40 is mainly generated, whereas under pathological conditions, Aβ42, the toxic form of Aβ, 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. Aβ leading to AD pathology (Jucker and Walker, 2011) can activate ASK1, which is required for ROS- and 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 anti-amyloid 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 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).
ASK1 in Parkinson's disease Parkinson's disease (PD) is the second-most-common neurodegenerative disorder after Alzheimer's disease, affecting 2–3% 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 α-synuclein. Its underlying molecular pathogenesis involves multiple pathways and mechanisms: α-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-3,4-dihydroxyphenylalanine) 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).