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http://purl.uniprot.org/citations/26125041http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26125041http://www.w3.org/2000/01/rdf-schema#comment"

Objective

Recent findings have shown that pharmacogenetic manipulations of the Ras-ERK pathway provide a therapeutic means to tackle l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). First, we investigated whether a prolonged l-DOPA treatment differentially affected ERK signaling in medium spiny neurons of the direct pathway (dMSNs) and in cholinergic aspiny interneurons (ChIs) and assessed the role of Ras-GRF1 in both subpopulations. Second, using viral-assisted technology, we probed Ras-GRF1 and Ras-GRF2 as potential targets in this pathway. We investigated how selective blockade of striatal Ras-GRF1 or Ras-GRF2 expression impacted on LID (induction, maintenance, and reversion) and its neurochemical correlates.

Methods

We used both Ras-GRF1 knockout mice and lentiviral vectors (LVs) delivering short-hairpin RNA sequences (shRNAs) to obtain striatum-specific gene knockdown of Ras-GRF1 and Ras-GRF2. The consequences of these genetic manipulations were evaluated in the 6-hydroxydopamine mouse model of Parkinson's disease. Escalating doses of l-DOPA were administered and then behavioral analysis with immunohistochemical assays and in vivo microdialysis were performed.

Results

Ras-GRF1 was found essential in controlling ERK signaling in dMSNs, but its ablation did not prevent ERK activation in ChIs. Moreover, striatal injection of LV-shRNA/Ras-GRF1 attenuated dyskinesia development and ERK-dependent signaling, whereas LV-shRNA/Ras-GRF2 was without effect, ruling out the involvement of Ras-GRF2 in LID expression. Accordingly, Ras-GRF1 but not Ras-GRF2 striatal gene-knockdown reduced l-DOPA-induced GABA and glutamate release in the substantia nigra pars reticulata, a neurochemical correlate of dyskinesia. Finally, inactivation of Ras-GRF1 provided a prolonged anti-dyskinetic effect for up to 7 weeks and significantly attenuated symptoms in animals with established LID.

Interpretation

Our results suggest that Ras-GRF1 is a promising target for LID therapy based on Ras-ERK signaling inhibition in the striatum."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.org/dc/terms/identifier"doi:10.1002/acn3.202"xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/author"Brambilla R."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/author"Fasano S."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/author"Morari M."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/author"Indrigo M."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/author"Solari N."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/author"D'Antoni A."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/author"Bido S."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/name"Ann Clin Transl Neurol"xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/pages"662-678"xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/title"Differential involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-induced dyskinesia."xsd:string
http://purl.uniprot.org/citations/26125041http://purl.uniprot.org/core/volume"2"xsd:string
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