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  • br Regulatory mechanisms of ASK activity br The


    Regulatory mechanisms of ASK1 activity
    The functions of ASK1 in disease
    ASK1 inhibitor As mentioned above, ASK1 plays a pivotal role in the pathogenesis of various diseases; hence, an ASK1 inhibitor has therapeutic potential. Although inhibitors of the ASK1 downstream kinases p38 and JNK are difficult to apply in clinical trials because of their severe side effects, an ASK1 inhibitor is expected to show only a limited effect because ASK1 knockout mice do not show distinct phenotypes compared with WT mice under basal conditions [21]. Therefore, in this section we provide a summary of the effects of some available ASK1 inhibitors in disease. MS1946002A was identified in a high-throughput screen, and lead optimization efforts led to the identification of MSC2032964A, which possesses a high selectivity and improved absorption, distribution, metabolism and excretion (ADME) profile. The effect of MSC2032964A was confirmed in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis; the disease course was ameliorated, reproducing the phenotype of ASK1 knockout mice [99]. In vitro effects on cytokine expression have been confirmed elsewhere [100]. K811 is another ASK1 inhibitor that is available for in vivo analysis. Because ASK1 had already been shown to be critical for the progression of amyotrophic lateral sclerosis (ALS) [101], the Colistin Sulfate receptor was applied to ALS model mice by oral administration. The results clearly indicated that K811 had a beneficial effect on the disease status, for which therapeutic modalities have been long awaited [102]. K811 has also been reported to have an effect on gastric cancer, allergic contact dermatitis and cognitive impairment [50], [103], [104]. Some other ASK1 inhibitors have also been reported, including GS-4997 for diabetic kidney disease [86], GS444217 for diabetic nephropathy [85], and NQDI-1 for ischemic injuries [96], [105], [106], some of which are being assessed in clinical trials. Various ASK1 inhibitors have been tested in vivo, as stated above, and exhibited certain effects, demonstrating their therapeutic potential for many diseases. To develop ASK1 inhibitors that more practical, some virtual screenings have recently been performed. Several methods can be used for virtual screening. One method is to search for new compounds that have similarities to known inhibitors. This method is easier than identifying new molecules [107]. An alternative in silico method utilizes the structure of ASK1, especially within the ATP-binding domain, driving the design of novel ASK1 inhibitors [108], [109], [110]. In addition to these technologies, further new techniques may be introduced, and a more effective ASK1 inhibitor could be developed in the future.
    Conclusion A post-translational modification (PTM) state of ASK1 is a pivotal feature for controlling ASK1 activity. One major PTM is phosphorylation; many kinases and phosphatases interact with ASK1 and control ASK1 activity by changing its phosphorylation state. Moreover, ubiquitination is also critical for ASK1 regulation, including K48-linked and K29-linked ubiquitination, and arginine methylation is another mechanism underlying the regulation of ASK1 activity [111], [112].
    Transparency document
    Acknowledgments This work was supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) (25221302) and Ono Medical Research Foundation.
    Introduction Leucine-rich repeat kinase 2 (LRRK2) is a serine/threonine (Ser/Thr) protein kinase that is homologous to receptor-interacting protein kinase and mixed-lineage kinase families belonging to the MAP3K superfamily, suggesting that it functions as an upstream regulator of mitogen-activated protein kinases (MAPK) [1], [2]. LRRK2 regulates MAPKs, including extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 MAPK [3]. In vitro studies have shown that LRRK2 interacts with and phosphorylates MAPK kinases MKK3/6 and MKK4/7 and consequently activates the ERK and p38 MAPK pathways [4], [5]. Several kinases, including apoptosis signal-regulating kinase 1 (ASK1), LRRK2, p38 MAPK, JNK3, and ERK, are involved in the pathogenesis of PD and are promising therapeutic targets for treating PD [6]. Patients with PD who harbor LRRK2 G2019S show higher relative activation of p38 MAPK than that of other MAPKs [7]. The association of LRRK2 with the p38 MAPK pathway was observed in human neuroblastoma cells in which LRRK2 G2019S induced the chronic activation of p38 MAPK [8]. In addition, the p38 MAPK pathway was activated in LRRK2 G2019S-expressing primary murine cortical neurons, which in turn increased their apoptosis and decreased their survival [8]. Similar results were observed in murine microglia showing a stable knockdown of Lrrk2 and DAT165 cells showing decreased LRRK2 expression in which phosphorylation of p38 MAPK was specifically attenuated compared with that in control cells [9], [10]. In the brain of patients with PD, active ASK1 is frequently colocalized with aberrant alpha-synuclein aggregates in the Lewy bodies, which is a hallmark of PD [11]. ASK1 is linked with PD toxins-induced cell death by phosphorylation of its downstream in cellular models of PD [12], [13], [14], [15]. ASK1 is a central kinase that integrates upstream signals to control neuronal apoptosis and is important for the pathogenesis of PD [16], [17], [18]. Despite this important insight into the role of ASK1 activation in neuronal apoptosis, no information is available on the regulating mechanisms of ASK1 in the pathogenesis of PD.