Exp Neurobiol.  2017 Apr;26(2):97-103. 10.5607/en.2017.26.2.97.

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

Affiliations
  • 1Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, OH 45701, USA. leed1@ohio.edu
  • 2Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
  • 3Center for Neuroscience, Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.

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.

Keyword

α-Synuclein; EKO; optogenetics; Parkinson's disease; Dopaminergic neurons; Drosophila melanogaster

MeSH Terms

alpha-Synuclein*
Brain
Dopamine
Dopaminergic Neurons
Drosophila
Drosophila melanogaster
Larva
Locomotion
Models, Genetic
Neurons
Optogenetics*
Parkinson Disease
Synaptic Transmission
Tyrosine
Dopamine
Tyrosine
alpha-Synuclein
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