The Kinase Fyn As a Novel Intermediate in l-DOPA-Induced Dyskinesia in Parkinson’s Disease

• Published in: Molecular neurobiology 2018-06, Vol.55 (6), p.5125-5136
• Main Authors: Sanz-Blasco, Sara, Bordone, Melina P., Damianich, Ana, Gomez, Gimena, Bernardi, M. Alejandra, Isaja, Luciana, Taravini, Irene R., Hanger, Diane P., Avale, M. Elena, Gershanik, Oscar S., Ferrario, Juan E.
• Format: Article
• Language: English
• Subjects: 6-Hydroxydopamine; Animals; Benzodioxoles - pharmacology; Biomedical and Life Sciences; Biomedicine; Cell Biology; Dihydroxyphenylalanine; Dopamine; Dopamine D1 receptors; Dyskinesia; Dyskinesia, Drug-Induced - complications; Dyskinesia, Drug-Induced - enzymology; Dyskinesia, Drug-Induced - pathology; Dyskinesia, Drug-Induced - physiopathology; Female; Fyn protein; Glutamic acid receptors (ionotropic); Levodopa; Male; Medical treatment; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Movement; N-Methyl-D-aspartic acid receptors; Neostriatum - metabolism; Neostriatum - pathology; Neurobiology; Neurology; Neurosciences; Parkinson Disease - complications; Parkinson Disease - enzymology; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson's disease; Phosphorylation; Postsynaptic density; Protein Subunits - metabolism; Protein-tyrosine kinase; Proto-Oncogene Proteins c-fyn - antagonists & inhibitors; Proto-Oncogene Proteins c-fyn - metabolism; Quinazolines - pharmacology; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Therapeutic applications; Tyrosine 3-Monooxygenase - metabolism
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-017-0748-3

Dopamine replacement therapy with l -DOPA is the treatment of choice for Parkinson’s disease; however, its long-term use is frequently associated with l -DOPA-induced dyskinesia (LID). Many molecules have been implicated in the development of LID, and several of these have been proposed as potential therapeutic targets. However, to date, none of these molecules have demonstrated full clinical efficacy, either because they lie downstream of dopaminergic signaling, or due to adverse side effects. Therefore, discovering new strategies to reduce LID in Parkinson’s disease remains a major challenge. Here, we have explored the tyrosine kinase Fyn, as a novel intermediate molecule in the development of LID. Fyn, a member of the Src kinase family, is located in the postsynaptic density, where it regulates phosphorylation of the NR2B subunit of the N -methyl- d -aspartate (NMDA) receptor in response to dopamine D1 receptor stimulation. We have used Fyn knockout and wild-type mice, lesioned with 6-hydroxydopamine and chronically treated with l -DOPA, to investigate the role of Fyn in the induction of LID. We found that mice lacking Fyn displayed reduced LID, ΔFosB accumulation and NR2B phosphorylation compared to wild-type control mice. Pre-administration of saracatinib (AZD0530), an inhibitor of Fyn activity, also significantly reduced LID in dyskinetic wild-type mice. These results support that Fyn has a critical role in the molecular pathways affected during the development of LID and identify Fyn as a novel potential therapeutic target for the management of dyskinesia in Parkinson’s disease.