br Experimental Procedures Additional information can be fou

Experimental Procedures Additional information can be found in Supplemental Experimental Procedures.
Author Contributions
Acknowledgments We thank all members of Lab of Health Chemistry for helpful discussions. This work was supported by Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) and the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), including KAKENHI on Innovative Areas “Oxygen Biology: a new criterion for integrated understanding of life” (No. 17H05518) of MEXT and KAKENHI on Innovative Areas “New aspect of the ubiquitin system: its enormous roles in protein regulation” (No. 15H01168) of MEXT, the Mitsubishi Foundation, the Shimabara Science Promotion Foundation, the Japan Foundation of Applied Enzymology, the Life Science Foundation of Japan, the Fugaku Trust for Medicinal Research, and the Takeda Science Foundation.
Introduction Neurodegenerative diseases (NDDs) are characterized by the progressive dysfunction and loss of 449 sale 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.