Optogenetic rescue of locomotor dysfunction and dopaminergic degeneration caused by alpha-synuclein and EKO genes

Cheng Qi, Scott Varga, Soo Jin Oh, Changjoon Lee, Daewoo Lee

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

A-Synuclein (A-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 A-Syn-mediated neurodegeneration in PD still remain to be explored. However, several studies strongly support that overexpression of mutant A-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 A-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 A-Syn and EKO. We believe this is for the first time to confirm that locomotion defects by a genetic PD factor such as A-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.

Original languageEnglish
Pages (from-to)97-103
Number of pages7
JournalExperimental Neurobiology
Volume26
Issue number2
DOIs
Publication statusPublished - 2017 Apr 1
Externally publishedYes

Keywords

  • A-Synuclein
  • Dopaminergic neurons
  • Drosophila melanogaster
  • EKO
  • Optogenetics
  • Parkinson's disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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