Articles

Article

Original Article

Exp Neurobiol 2017; 26(2): 97-103

Published online April 30, 2017

https://doi.org/10.5607/en.2017.26.2.97

© The Korean Society for Brain and Neural Sciences

Optogenetic Rescue of Locomotor Dysfunction and Dopaminergic Degeneration Caused by Alpha-Synuclein and EKO Genes

Cheng Qi1, Scott Varga1, Soo-Jin Oh2,3, C. Justin Lee3 and Daewoo Lee1*

1Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, OH 45701, USA, 2Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, 3Center for Neuroscience, Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 1-740-597-1926, FAX: 1-740-593-0300
e-mail: leed1@ohio.edu

Received: March 28, 2017; Revised: April 12, 2017; Accepted: April 12, 2017

Abstract

α-Synuclein (α-Syn) is a small presynaptic protein and its mutant forms (e.g. A53T) are known to be directly associated with Parkinson's disease (PD). Pathophysiological mechanisms underlying α-Syn-mediated neurodegeneration in PD still remain to be explored. However, several studies strongly support that overexpression of mutant α-Syn causes reduced release of dopamine (DA) in the brain, and contributes to motor deficits in PD. Using a favorable genetic model Drosophila larva, we examined whether reduced DA release is enough to induce key PD symptoms (i.e. locomotion deficiency and DA neurodegeneration), mimicking a PD gene α-Syn. In order to reduce DA release, we expressed electrical knockout (EKO) gene in DA neurons, which is known to make neurons hypo-excitable. EKO led to a decrease in a DA neuronal marker signal (i.e., TH – tyrosine hydroxylase) and locomotion deficits in Drosophila larva. In contrast, acute and prolonged exposure to blue light (BL, 470 nm) was sufficient to activate channelrhodopsin 2 (ChR2) and rescue PD symptoms caused by both α-Syn and EKO. We believe this is for the first time to confirm that locomotion defects by a genetic PD factor such as α-Syn can be rescued by increasing DA neuronal excitability with an optogenetic approach. Our findings strongly support that PD is a failure of DA synaptic transmission, which can be rescued by optogenetic activation of ChR2.

Keywords: α-Synuclein, EKO, optogenetics, Parkinson’s disease, Dopaminergic neurons, Drosophila melanogaster