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

Abstract

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.

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Acknowledgments

This work has been entirely done with grants provided from non-profit foundations or organizations as well as Argentine research institutions: EMBO short-term fellowship (JEF, 2012), IBRO Return Home Fellowship (JEF, 2013), ISN CAEN Return Home Grant (SSB, 2014), ANPCYT-PICT (OG 2011–1758), CONICET-PIP (JEF&IT, 2013–0401), and Michael J. Fox Foundation for Parkinson’s Research, Target Validation Spring 2014 (JEF & OG,). We thank Gustavo Murer for critical review of the manuscript, Mariano Saborido for obtaining preliminary data, and Soledad Campana and Natalia Baffa-Trasci for technical assistance.

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Correspondence to Oscar S. Gershanik or Juan E. Ferrario.

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All surgical procedures and experimental manipulations were performed in accordance with the UK Home Office and the European Directive 2010/63/EU and approved by the Ethics Committee of “Facultad de Farmacia y Bioquímica” (Universidad de Buenos Aires, Argentina).

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Sanz-Blasco, S., Bordone, M.P., Damianich, A. et al. The Kinase Fyn As a Novel Intermediate in l-DOPA-Induced Dyskinesia in Parkinson’s Disease. Mol Neurobiol 55, 5125–5136 (2018). https://doi.org/10.1007/s12035-017-0748-3

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Keywords

  • Parkinson’s disease
  • l-DOPA
  • Dyskinesias
  • Fyn
  • NR2B
  • Saracatinib