Levodopa-Induced Motor and Dopamine Receptor Changes in <b><i>Caenorhabditis elegans</i></b> 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.

Caffeine reduces deficits in mechanosensation and locomotion induced by L-DOPA and protects dopaminergic neurons in a transgenic Caenorhabditis elegans model of Parkinson’s disease

“…Ergo, exposure to 60 mM L-DOPA recovers the motor response, before the worm can grow tolerant once again. A previous study reported hyperactivity with lack of purpose in L-DOPA-treated C. elegans (Gupta et al 2016), which was consistent with our study showing greater locomotion scores but with increasing neurodegeneration. the latter being the probable reason for the loss in prudent locomotion.…”

Anti‐Parkinson's Disease Function of Dioscin‐Zein‐Carboxymethyl Cellulose Nanocomplex in Caenorhabditis elegans

“…CAT-2 (tyrosine 3-monooxygenase) catalyzes the conversion of tyrosine (Tyr) to L-DOPA. [17,25] Therefore, DA is rarely produced in the CB1112 strain with loss-of-function mutation in cat-2 through this major pathway. As shown in BSR and alcohol avoidance assay (Figure 4B and Figure S7, Supporting Information), these typical DA behaviors were completely disappeared in cat-2 mutant worms suggesting a correspondence to the function of Cat-2 in the DA metabolism pathway.…”

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

“…Therefore, both PD and LID are caused by dysfunctional DA signaling although PD is due to reduced DA signaling while LID is by increased and uncoordinated DA activities. Recently, it has been shown that hyperkinetic activity and altered D1 signaling underlie L-DOPA induced dyskinesia in C. elegans [ 28 ], further supporting the notion that uncontrollable DA signaling is a key pathological mechanism of LID. One important factor considering use of Drosophila model for LID is the similarity of DA signaling mechanisms in mammals and Drosophila.…”

“…Previously, there were few LID models which can be used to study underlying pathophysiological mechanisms, genetic/molecular targets initiating the development of LID, and potential pharmacological therapies [ 27 ], largely due to lack of rich genetic resources. Recently, Gupta et al [ 28 ] has been developed C. elegans LID model expressing human α-synuclein, which shows increase body bending with L-DOPA. Overall, 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 and/or reverse LID pathology.…”