Team:KOREA/Design
Design
Parkinson’s diseases is a typical neurodegenerative diseases, which lots of elderly people are suffering from it. Parkinson’s disease occurs overall weakened motor ability including hand tremors, muscle stiffness, posture instability, slowed motor speed. Depression, dementia and narcolepsy can be involved. Variety of nervous system disorders result in excretion/sexual dysfunction and sensory abnormalities. Parkinson’s disease is difficult to cure because the patients must take medicine or invasive treatments until death.
Levodopa, the Imperfect treatment
Levodopa, the dopamine precursor, is the most effective drug for Parkinson's disease. However, if levodopa is used for more than 5 years, the effect is weakened. Moreover, it could trigger dyskinesia, the broad motor disturbance. Vomiting, anorexia, hallucination, hyper-tension, and depression are also reported as side effects of levodopa.How to figure out this problem?
As mentioned before, our goal is to cure Parkinson's disease by optogenetics. Light has high spatio-temporal accuracy. Also, the reaction using light method is reversible by turning it off or light it up. To do this, we fused the human opsin protein as a light sensor and Dopamine Receptor D2.
Dopamine Receptor D2(DRD2) is the most common dopamine receptor. It is one of GPCR(G-protein coupled receptor), so it has seven helixes. When dopamine binds to its outer domain, its inner domain will activate the guanine nucleotide-binding protein. Then a series of reactions called dopamine signaling pathways occur. Parkinson's disease patients have dopamine deficiency, which causes DRD2 to be activated at a low frequency. Consequently, this pathway rarely transpires. We focused on the idea of activating DRD2 without dopamine.
Both opsin and DRD2 are homologous and GPCR which has 7 transmembrane regions. The extracellular and trans-membrane domains are from opsin’s, and the inner membrane domains are from DRD2. When externally injected retinal binds to opsin, the optical activity of the opsin stimulates the DRD2 inside the membrane. Therefore, light can activate the dopamine signaling pathway without genuine dopamine.
The image above shows a schematic of our fusion protein. When light converts the retinal structure, the opsin domain that binds to the retinal also changes its structure. This change also affects the intra-cellular DRD2 domains, which gradually activates the dopamine pathway.
Experimental Procedures
