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Open Access 01-08-2018 | Neurology and Preclinical Neurological Studies - Review Article

Signal transduction in l-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression

Authors: Giada Spigolon, Gilberto Fisone

Published in: Journal of Neural Transmission | Issue 8/2018

Abstract

A large number of signaling abnormalities have been implicated in the emergence and expression of l-DOPA-induced dyskinesia (LID). The primary cause for many of these changes is the development of sensitization at dopamine receptors located on striatal projection neurons (SPN). This initial priming, which is particularly evident at the level of dopamine D1 receptors (D1R), can be viewed as a homeostatic response to dopamine depletion and is further exacerbated by chronic administration of l-DOPA, through a variety of mechanisms affecting various components of the G-protein-coupled receptor machinery. Sensitization of dopamine receptors in combination with pulsatile administration of l-DOPA leads to intermittent and coordinated hyperactivation of signal transduction cascades, ultimately resulting in long-term modifications of gene expression and protein synthesis. A detailed mapping of these pathological changes and of their involvement in LID has been produced during the last decade. According to this emerging picture, activation of sensitized D1R results in the stimulation of cAMP-dependent protein kinase and of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa. This, in turn, activates the extracellular signal-regulated kinases 1 and 2 (ERK), leading to chromatin remodeling and aberrant gene transcription. Dysregulated ERK results also in the stimulation of the mammalian target of rapamycin complex 1, which promotes protein synthesis. Enhanced levels of multiple effector targets, including several transcription factors have been implicated in LID and associated changes in synaptic plasticity and morphology. This article provides an overview of the intracellular modifications occurring in SPN and associated with LID.

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Title: Signal transduction in l-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression
Authors: Giada Spigolon
Gilberto Fisone
Publication date: 01-08-2018
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 8/2018
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-018-1847-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Signal transduction in l-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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