Optogenetic Rescue of Locomotor Dysfunction and Dopaminergic Degeneration Caused by Alpha-Synuclein and EKO Genes.
- Author:
Cheng QI
1
;
Scott VARGA
;
Soo Jin OH
;
C Justin LEE
;
Daewoo LEE
Author Information
- Publication Type:Original Article
- Keywords: α-Synuclein; EKO; optogenetics; Parkinson's disease; Dopaminergic neurons; Drosophila melanogaster
- MeSH: alpha-Synuclein*; Brain; Dopamine; Dopaminergic Neurons; Drosophila; Drosophila melanogaster; Larva; Locomotion; Models, Genetic; Neurons; Optogenetics*; Parkinson Disease; Synaptic Transmission; Tyrosine
- From:Experimental Neurobiology 2017;26(2):97-103
- CountryRepublic of Korea
- Language:English
- 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.
