Institute of Biological Chemistry, Academia Sinica

Increased oxidative stress is considered to be one of the key factors leading to aging and neurodegenerative diseases, but it is not clear why oxidative stress can accumulate in the nervous system and affect the functioning of the nervous system. A recent study by the research team led by Chi-Kuang Yao, an assistant research fellow at the Institute of Biological Chemistry, found a new model of oxidative stress propogation. This team demonstrated that oxidative stress can promote its own formation and further damage entire motor nervous system function through the connecting properties of the motor circuit. This achievement will open a new window for related research on motor system dysfunction caused by aging and motor neuron diseases. The paper was published in eLife on July 18.

The human central nervous system establishes a complex neural circuit system by connecting a large number of neurons to each other. These loop systems drive complex but rhythmic and coordinated behaviors such as walking, running and swimming by activating skeletal muscle contractions. The neural circuit system communicates with the muscles. If an imbalance occurs, it will cause serious illness. These systems consume more energy to function properly than other tissues in the human body. When the cell is productive, the reactive oxygen species (ROS) are known to be accompanied by release. When facing with aging or neurodegenerative diseases, excessive ROS (commonly known as oxidative stress) are often elicited, which in turn affects neuronal function and reduces overall nervous system function. Glutamate is the major excitatory neurotransmitter that controls most of the activity of the human nervous system. Therefore, the tight balance between its release and uptake is the key to the proper functioning of the nervous system. Excess glutamate accumulation is common in neurologically related diseases, which cause excessive nervous system activation and is therefore called glutamate excitotoxicity. It is worth mentioning that glutamate excitotoxicity is one of the main causes of increased oxidative stress. However, it has not yet been understood how oxidative stress interferes with the operation of neural networks.

The research team led by Dr. Chi-Kuang Yao has used the motor circuit of Drosophila larvae as a research system to solve this challenging problem in recent years. Drosophila larvae can use the rhythmic and coordinated crawling movements for feeding, which is similar to human walking, running and swimming. This behavior is controlled by the motor circuit. The motor circuit of Drosophila larvae is relatively simple compared to the human motor circuit, but has high functional conservation. Therefore, it is very suitable for studying the mechanism regulating the motor circuit. (As shown in figure) This team found that when glutamate excitotoxicity oxidative stress increases to alter the normal activity of the motor circuit, causing overstimulation of the motor neurons and muscles. Notably, tonic stimulation of motor neurons in turn increases oxidative stress in the muscles to gradually inhibit muscle contractility and hence impair sensory feedback, which in turn enhances the accumulation of oxidative stress in the motor circuit, thereby exacerbating circuit dysfunction. Ultimately, excessive stimulation of motor neurons activates the cellular signaling pathway regulated by oxidative stress, which alters the connectivity of motor neurons and muscles. These findings unravel the glutamate excitotoxicity that can cause a neural circuit-dependent oxidative stress feedback loop to affect the normal functioning of the entire motor system. The above deficits can also be alleviated by feeding of antioxidant (AD4) and potassium channel antagonist (4-AP). In the future, the key research direction is to clarify whether the abovementioned machine can be applied to age-dependent motor function decline and the pathogenesis of motor neuron diseases, such as amyotrophic lateral sclerosis (ALS). The results of this latest and follow-up study are expected to provide feasible preventive and therapeutic strategies to these urgent social health issues.

The research was jointly supported by the Academia Sinica and the Ministry of Science and Technology. Dr. Chi-Kuang Yao research team includes the first authors Jhan-Jie Peng and Shih-Han Lin, as well as other authors including Yu-Tzu Liu, Hsin-Chieh Lin, and Tsai-Ning Lee Liu.

Article title: “A circuit-dependent ROS feedback loop mediates glutamate excitotoxicity to sculpt the Drosophila motor system”

The full article is available at: https://elifesciences.org/articles/47372

Authors:Peng JJ, Lin SH, Liu YT, Lin HC, Li TN, Yao CK*

Updated: 2019.07.26