Increase in reactive oxygen species (ROS) leading to human amyotrophic lateral sclerosis (ALS)

Shihori Tanabe¹, Satoru Morimoto², Yoshitsugu Aoki³, Shinichi Takahashi^2,4, Katarina Živančević⁵, Minoru Sakuragi⁶, Yasushi Okuno⁶, Hideyuki Okano², Horacio Cabral⁷

1. National Institute of Health Sciences, Japan

2. Keio University Regenerative Medicine Research Center, Japan

3. National Center of Neurology and Psychiatry (NCNP), Japan

4. Saitama Medical University International Medical Center, Japan

5. University of Belgrade, Republic of Serbia

6. Kyoto University, Japan

7. The University of Tokyo, Japan  

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the impairment of motor neurons in the brain and spinal cord, leading to skeletal muscle atrophy and eventual death due to respiratory muscle paralysis. Currently, fundamental curative treatments remain unestablished. The objective of this study is to develop an Adverse Outcome Pathway (AOP) for ALS to elucidate its underlying pathological mechanisms. By analyzing molecular networks using RNA-seq data and synthesizing existing literature, we have proposed a draft AOP. This pathway delineates the progression from an initial rise in reactive oxygen species (ROS) and oxidative stress to neurodegeneration and motor neuron death, mediated by key events such as TDP-43 aggregation, mitochondrial dysfunction, neuroinflammation, and axonal transport failure. In developing a quantitative AOP (qAOP), it is essential to assess the quantifiability of each Key Event (KE) and Key Event Relationship (KER) to accurately model the network's functional relationships. Current AOP636 starts with MIE1115, an increase in ROS, links to KE177, an increase in mitochondrial dysfunction, KE188, neuroinflammation, and KE386, a decrease in neuronal network function, and leads to AO2416 human ALS. We need to develop a new KE2416 on ALS and KERs with a quantitative understanding.