br Conclusions A large body of evidence

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
Overall characteristics Apoptosis signal-regulating kinase 1 (ASK1) was initially identified as a mitogen-activated protein kinase kinase kinase (MAP3K) and shown to selectively activate the c-Jun N-terminal kinase (JNK) and p38 pathways [1]. Various stressors activate ASK1, including endoplasmic reticulum (ER) stress, heat shock, and osmotic stress, as well as inflammatory cytokines and lipopolysaccharide (LPS). Among these stressors, one of the most potent activators of ASK1 is oxidative stress. ASK1 plays a pivotal role in apoptotic cell death induced by H2O2. (See Fig. 1.) Mouse ASK1 consists of 1380 fiin (human ASK1 has 1374 amino acids) and possesses a serine/threonine kinase domain in its middle region and flanking long N- and C-terminal regulatory domains [1], [2]. The primary sequence of the kinase domain is highly conserved from the Caenorhabditis elegans ortholog NSY-1 to human ASK1, including a characteristic cluster of threonine residues in the activation loop located in the linkage region between subdomains VII and VIII. One of the threonine residues (Thr845 and Thr838 in mouse and human ASK1, respectively) is essential for ASK1 kinase activity, and phosphorylation at this site tightly regulates the activation of ASK1. The phosphorylation appears to be mediated by an unknown upstream kinase; however, intermolecular autophosphorylation also provides a substantial contribution, as evidenced by the dramatic suppression of threonine residue phosphorylation in a kinase-dead mutant of ASK1 [3]. ASK1 is highly sensitive to H2O2 in diverse cell types, and many studies have revealed the precise mechanism of H2O2-dependent ASK1 activation. ASK1 activation requires homo-oligomerization through its C-terminal coiled-coil (CCC) domain [3]. A subsequent study revealed that ASK1 forms a high-molecular-mass (HMM) complex (> 1500kDa) through the CCC domain with relatively high basal activity in the cell, even under unstimulated conditions. When a kinase-negative mutant of ASK1 is expressed in cells, it also forms a HMM complex, whereas an ASK1 mutant lacking the CCC domain forms a smaller complex (~500kDa; but still larger than monomeric ASK1) with no detectable activity. These findings suggest that homo-oligomerization, not kinase activity, is critical for HMM complex formation, which is required for ASK1 activity. Furthermore, the HMM complex increases in size in response to H2O2, forming an even higher mass complex. Because this preformed HMM complex appears to serve as a platform for the regulation of basal activity and even stress-induced activation of ASK1, this functional complex was designated the ASK1 signalosome [4]. ASK1 interacts with diverse molecules in a context-dependent manner; however, only recently have the details of the composition of the ASK1 signalosome been elucidated. One group used precise stable isotope dilution assays to quantify the protein stoichiometry in the ASK1 signalosome and identified the stoichiometric ratio of several components to ASK1; for example, ASK2 at a 1:1 ratio with ASK1 and 14‐3-3 proteins at 0.5:1 [5]. In this review, we will provide a detailed discussion of the function of the ASK1 signalosome.