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Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia
Chiara Melis1, Genevieve Beauvais2, Brian S Muntean3
1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Background:
Similar to some monogenic forms of dystonia, levodopa-induced dyskinesia is a hyperkinetic movement disorder with abnormal nigrostriatal dopaminergic neurotransmission. Molecularly, it is characterized by hyper-induction of phosphorylation of extracellular signal-related kinase in response to dopamine in medium spiny neurons of the direct pathway.
Objectives:
The objective of this study was to determine if mouse models of monogenic dystonia exhibit molecular features of levodopa-induced dyskinesia.
Methods:
Western blotting and quantitative immunofluorescence was used to assay baseline and/or dopamine-induced levels of the phosphorylated kinase in the striatum in mouse models of DYT1, DYT6, and DYT25 expressing a reporter in dopamine D1 receptor-expressing projection neurons. Cyclic adenosine monophosphate (cAMP) immunoassay and adenylyl cyclase activity assays were also performed.
Results:
In DYT1 and DYT6 models, blocking dopamine reuptake with cocaine leads to enhanced extracellular signal-related kinase phosphorylation in dorsomedial striatal medium spiny neurons in the direct pathway, which is abolished by pretreatment with the N-methyl-d-aspartate antagonist MK-801. Phosphorylation is decreased in a model of DYT25. Levels of basal and stimulated cAMP and adenylyl cyclase activity were normal in the DYT1 and DYT6 mice and decreased in the DYT25 mice. Oxotremorine induced increased abnormal movements in the DYT1 knock-in mice.
Conclusions:
The increased dopamine induction of extracellular signal-related kinase phosphorylation in 2 genetic types of dystonia, similar to what occurs in levodopa-induced dyskinesia, and its decrease in a third, suggests that abnormal signal transduction in response to dopamine in the postsynaptic nigrostriatal pathway might be a point of convergence for dystonia and other hyperkinetic movement disorders, potentially offering common therapeutic targets. © 2021 International Parkinson and Movement Disorder Society.
Insights
Levodopa-induced dyskinesia and some dystonia forms share molecular similarities in dopamine signaling pathways. This study found altered extracellular signal-related kinase phosphorylation in mouse models, suggesting common therapeutic targets for hyperkinetic movement disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Levodopa-induced dyskinesia is a hyperkinetic movement disorder linked to abnormal dopamine signaling.
- This condition involves hyper-phosphorylation of extracellular signal-related kinase (ERK) in medium spiny neurons.
Purpose of the Study:
- To investigate if mouse models of monogenic dystonia display molecular features similar to levodopa-induced dyskinesia.
- To explore the role of dopamine signaling and ERK phosphorylation in different dystonia models.
Main Methods:
- Utilized Western blotting and immunofluorescence to assess ERK phosphorylation in striatum of DYT1, DYT6, and DYT25 mouse models.
- Performed cyclic adenosine monophosphate (cAMP) assays and adenylyl cyclase activity tests.
- Administered MK-801 and oxotremorine to evaluate drug effects on movement and signaling.
Main Results:
- Enhanced ERK phosphorylation was observed in DYT1 and DYT6 models upon dopamine reuptake blockade, reversible with MK-801.
- Decreased ERK phosphorylation and cAMP levels were noted in the DYT25 model.
- Oxotremorine exacerbated abnormal movements in DYT1 mice.
Conclusions:
- Altered dopamine-induced ERK phosphorylation in the nigrostriatal pathway is a shared feature between certain dystonia types and levodopa-induced dyskinesia.
- These findings suggest common signal transduction pathways as potential therapeutic targets for hyperkinetic movement disorders.
