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L-DOPA-Induced Dyskinesia in a Genetic Drosophila Model of Parkinson’s Disease

Experimental Neurobiology 2020년 29권 4호 p.273 ~ 284
Blosser Joshua A., Podolsky Eric, 이대우,
소속 상세정보
 ( Blosser Joshua A. ) - Ohio University Department of Biological Sciences Neuroscience Program
 ( Podolsky Eric ) - Ohio University Department of Biological Sciences Neuroscience Program
이대우 ( Lee Dae-Woo ) - Ohio University Department of Biological Sciences Neuroscience Program

Abstract


Motor symptoms in Parkinson’s disease (PD) are directly related to the reduction of a neurotransmitter dopamine. Therefore, its precursor L-DOPA became the gold standard for PD treatment. However, chronic use of L-DOPA causes uncontrollable, involuntary movements, called L-DOPA-induced dyskinesia (LID) in the majority of PD patients. LID is complicated and very difficult to manage. Current rodent and non-human primate models have been developed to study LID mainly using neurotoxins. Therefore, it is necessary to develop a LID animal model with defects in genetic factors causing PD in order to study the relation between LID and PD genes such as α-synuclein. In this study, we first showed that a low concentration of L-DOPA (100 μM) rescues locomotion defects (i.e., speed, angular velocity, pause time) in Drosophila larvae expressing human mutant α-synuclein (A53T). This A53T larval model of PD was used to further examine dyskinetic behaviors. High concentrations of L-DOPA (5 or 10 mM) causes hyperactivity such as body bending behavior (BBB) in A53T larva, which resembles axial dyskinesia in rodents. Using ImageJ plugins and other third party software, dyskinetic BBB has been accurately and efficiently quantified. Further, we showed that a dopamine agonist pramipexole (PRX) partially rescues BBB caused by high L-DOPA. Our Drosophila genetic LID model will provide an important experimental platform to examine molecular and cellular mechanisms underlying LID, to study the role of PD causing genes in the development of LID, and to identify potential targets to slow/reverse LID pathology.

키워드

Alpha-Synuclein; Parkinson’s disease; L-DOPA; Dyskinesia; Drosophila melanogaster

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