To Investigate the Role of Dopamine Receptor D2R and Adenosine Receptor A2AR in Amyotrophic Lateral Sclerosis Disease Models

• Main Authors: LAI, JIA-YOU, 賴佳攸
• Other Authors: Chern, YI-JUANG
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/a55jb7

博士 === 國防醫學院 === 生命科學研究所 === 106 === Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease. The pathogenesis of neuronal damage is still not fully understood. TAR-DNA binding protein-43 (TDP-43), a nuclear protein is recently reported to abnormally localize in the cytoplasm of motor neurons in ALS patients. Increasing oxidative stress or gene mutations have been pointed out to induce TDP-43 mislocalization and may contribute to the initial steps of motor neuron damage. AMP-activating protein kinase (AMPK) is the downstream signal of oxidative stress. A2AR agonists inhibition of AMPK activity improves the motor function of mice with neurodegenerative diseases, such as in Huntington's disease and ALS disease (TDP-43). T1-11 is an A2AR agonist and an ENT1 inhibitor, which is extracted from Chinese herbal. In a motorneuron cell line (NSC34), T1-11 blocked oxidative stress (ROS)-induce TDP-43 mislocalization. Because A2AR and D2R form dimer complex that negatively regulate each receptors functions in the striatal region. A2AR and D2R has been found in the motor neuron of spinal cord, but their interaction, such is dimer complex formation has not been investigated. In this current study, I want to investigate whether D2R interferes the beneficial effects of A2AR on motor neurons. I demonstrated that A2AR and D2R are expressed in mouse and human spinal motor neurons. The A2AR and D2R complex did not affect the binding affinity of T1-11 to A2AR. Most importantly, activation of D2R diminished T1-11-induce cAMP/ PKA signal and blocked T1-11 inhibition of ROS-induce TDP-43 mislocalization. In an ALS mouse model, combined administration of Quinpirole (a D2R activator) attenuates T1-11 beneficial effects on TDP-43 mislocalization and grip performance. Taken together, my study indicate that activation of A2AR plays an important role in the pathogenesis of ALS, however, simultaneous activation of dopamine receptor D2R may limit the beneficial response of an A2AR agonist in motor neurons. Because ALS patients are accompanied by depression and anxiety, D2R activators are usually used to treat mentally related diseases (such as depression). Therefore, mutual drug interference of A2AR activator and D2R activator should be considered in clinical treatment of ALS patients.