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

Authors :
Soo Jin Oh
Daewoo Lee
Scott J. Varga
Cheng Qi
C. Justin Lee
Source :
Experimental Neurobiology
Publication Year :
2017
Publisher :
The Korean Society for Brain and Neural Science, 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.

Details

Language :
English
ISSN :
20938144 and 12262560
Volume :
26
Issue :
2
Database :
OpenAIRE
Journal :
Experimental Neurobiology
Accession number :
edsair.doi.dedup.....dd7cba8e8c26b48c990826fc632295de