title: Levodopa-Induced Motor and Dopamine Receptor Changes in Caenorhabditis elegans Overexpressing Human Alpha-Synuclein.
abstract: BACKGROUND
  Levodopa-induced dyskinesia (LID) is a disabling complication of levodopa therapy in Parkinson's disease (PD) with no effective treatments. Fluctuations in levels of levodopa constitute a key risk factor of LID. There is a pressing need for the development of a simple animal model of LID. Several genetic and toxin-based models of PD in Caenorhabditis elegans have been described, which have advanced our understanding of PD pathophysiology. We aimed to study levodopa-induced changes in a Parkinson's disease model of C. elegans expressing human α-synuclein.
  
  
  METHODS
  We exposed the α-synuclein C. elegans to levodopa in continuous and alternating fashions. Automated behavioral analysis was then used to quantify changes in motor activity. Confocal microscopy was used next to quantify changes in dopamine receptor distribution and expression in motor neurons of live C. elegans.
  
  
  RESULTS
  Chronic exposure to levodopa led to hyperactivity of the α-synuclein C. elegans without meaningful increase in motor activity. There was also an increase in peripheral clustering and expression of dopamine receptors in motor neurons. Both of these changes were significantly higher with alternating, compared to continuous, exposure to levodopa.
  
  
  CONCLUSIONS
  This is the first report of changes in motor and dopamine receptors induced by levodopa in C. elegans overexpressing human α-synuclein. We propose that these phenotypes represent a simple animal model of LID in C. elegans. Such a model holds the promise of enabling high-throughput screenings for potential therapeutic targets and drug candidates.
authors.affiliation: Department of Neurology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Gupta
authors.forename: Xi
authors.initials: X
authors.lastname: Hang
authors.forename: Ruifu
authors.initials: R
authors.lastname: Liu
authors.forename: Armaan
authors.initials: A
authors.lastname: Hasan
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Feng
mesh_terms: D056044:Actigraphy; D000818:Animals; D030801:Animals, Genetically Modified; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000633:toxicity*; D017173:Caenorhabditis elegans; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007980:Levodopa / Q000494:pharmacology / Q000633:toxicity*; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010363:Pattern Recognition, Automated; D011954:Receptors, Dopamine / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D011954:Receptors, Dopamine; C497604:SNCA protein, human; D051844:alpha-Synuclein; D007980:Levodopa