TY - JOUR
T1 - Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia
AU - Melis, Chiara
AU - Beauvais, Genevieve
AU - Muntean, Brian S.
AU - Cirnaru, Maria Daniela
AU - Otrimski, Garrett
AU - Creus-Muncunill, Jordi
AU - Martemyanov, Kirill A.
AU - Gonzalez-Alegre, Pedro
AU - Ehrlich, Michelle E.
N1 - Funding Information:
C.M., G.B., B.S.M., G.O., and J.C.‐M. have nothing to report. M.‐D.C. reports research funding from the Dystonia Research Medical Foundation. K.A.M. reports research funding from the National Institutes of Health (NIH). P.G.‐A. has received consulting fees unrelated to this work from Spark Therapeutics, Eisai Therapeutics, and NeuExcell; research funding from the NIH; and funds from clinical trial execution from CHDI and BioHaven. M.E.E. reports research funding from the NIH.
Funding Information:
This work was supported by the National Institutes of Health grants R21 NS107883 (to P.G.‐A.), DA036596 (to K.A.M.), and R01 NS081282 (to M.E.E. and K.A.M.), and a fellowship from the Dystonia Medical Research Foundation to M.‐D.C. Funding agencies:
Publisher Copyright:
© 2021 International Parkinson and Movement Disorder Society
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - ERK
KW - dopamine
KW - dystonia
KW - levodopa-induced dyskinesia
KW - map kinase
KW - striatum
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U2 - 10.1002/mds.28476
DO - 10.1002/mds.28476
M3 - Article
C2 - 33458877
AN - SCOPUS:85099372248
VL - 36
SP - 1147
EP - 1157
JO - Movement Disorders
JF - Movement Disorders
SN - 0885-3185
IS - 5
ER -