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Shp‐2 knockdown prevents l ‐dopa‐induced dyskinesia in a rat model of Parkinson's disease
Author(s) -
Fiorentini Chiara,
Savoia Paola,
Savoldi Daria,
Bono Federica,
Busi Chiara,
Barbon Alessandro,
Missale Cristina
Publication year - 2016
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.26581
Subject(s) - dyskinesia , gene knockdown , kinase , striatum , extracellular , downregulation and upregulation , phosphorylation , pharmacology , receptor , chemistry , microbiology and biotechnology , parkinson's disease , dopamine , biology , neuroscience , medicine , biochemistry , apoptosis , disease , gene
Background Dyskinesia, the major side effect of l ‐dopa therapy in PD, is mainly associated with nonphysiological stimulation of denervated receptors in the striatum. In particular, DA D1 receptor‐mediated aberrant extracellular signal‐regulated protein kinases 1 and 2 activation have been associated with striatal changes leading to dyskinesia. We recently identified the tyrosine phosphatase Shp‐2 as a crucial effector transmitting D1 receptor signaling to extracellular signal‐regulated protein kinases 1 and 2 activation and reported the involvement of the D1 receptor/Shp‐2/extracellular signal‐regulated protein kinases 1 and 2 pathway in the development of l ‐dopa‐induced dyskinesia. Objectives In this study, the role of Shp‐2 in l ‐dopa‐induced dyskinesia development was investigated by in vivo silencing of Shp‐2 in the striatum of the 6‐hydroxy‐dopamine rat model of PD. Methods Lentiviral particles delivering short hairpin RNA were used to obtain long‐term striatal Shp‐2 downregulation. Rats were then treated with l ‐dopa and analyzed for both the improvement of akinesia and the development of l ‐dopa‐induced dyskinesia. Results The results show that Shp‐2 knockdown remarkably decreased extracellular signal‐regulated protein kinases 1 and 2 phosphorylation and attenuated the severity of l ‐dopa‐induced dyskinesia likely without compromising the therapeutic efficacy of l ‐dopa. Conclusion These data suggest that the striatal D1 receptor/Shp‐2 complex may represent a promising novel target for the development of antidyskinetic drugs. © 2016 International Parkinson and Movement Disorder Society