L-DOPA-induced signaling pathways and neuroepigenetic mechanisms in experimental parkinsonism and dyskinesia

In patients with Parkinson’s disease (PD), the restoration of depleted striatal dopamine by chronic administration of its precursor, L-DOPA, results in the emergence of debilitating involuntary movements. This complication, termed L-DOPA-induced dyskinesia (LID), represents a limitation to the most efficacious treatment for PD motor symptoms. LID progressively increases in severity despite the continual ability of L-DOPA to alleviate parkinsonian symptoms, suggesting divergent mechanisms of action and the potential for therapeutic intervention. Utilizing an experimental mouse model of PD, the work presented within this thesis investigates the molecular alterations underlying LID. These studies reveal that L-DOPA administration results in pathological intracellular signaling and gene expression within striatal medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R).

Following L-DOPA administration, sensitized D1R signaling results in hyperactivity of the cyclic 3’-5’ adenosine monophosphate (cAMP)/cAMP-dependent kinase (PKA)/ dopamine- and cAMP-regulated phosphoprotein of 32 kDA (DARPP-32) pathway. This exaggerated response results in excessive activation of the downstream extracellularregulated kinases 1 and 2 (ERK1/2) and mammalian target of rapamycin complex 1 (mTORC1) cascades, both of which are implicated in LID. These data also demonstrate that nuclear events mediated by mitogen- and stress-activated kinase 1 (MSK1), a direct ERK1/2 substrate, promote the induction of the transcription factor ΔFosB, which exacerbates LID. Furthermore, the concerted activity of MSK1 and DARPP-32 promotes histone H3K27me3S28p and the dissociation from transcription start sites of Rnf2, a Polycomb group protein that represses gene expression.

These events are associated with an increase in transcription. Taken together, these studies support the idea that sensitized striatal D1R signaling promotes LID by excessive activation of intracellular signaling pathways and nuclear events promoting gene expression.

List of scientific papers

I. Santini E, Feyder M, Gangarossa G, Bateup HS, Greengard P, Fisone G (2012) Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism. J Biol Chem. 287: 27806-27812.
https://doi.org/10.1074/jbc.m112.388413

II. Feyder M, Södersten E, Santini E, Vialou V, LaPlant QC, Watts EL, Spigolon G, Hansen K, Caboche J, Nestler EJ and Fisone G. A role for mitogen- and stress-activated kinase 1 in L-DOPA-induced dyskinesia and ΔFosB expression. Biol Psychiatry. [Accepted]
https://doi.org/10.1016/j.biopsych.2014.07.019

III. Södersten E, Feyder M, Lerdrup M, Gomes A, Kryh H, Spigolon G, Caboche J, Fisone G, Hansen K (2014). Dopamine signaling leads to loss of polycomb repression and aberrant gene activation in experimental parkinsonism. PLOS Genetics. 10(9).
https://doi.org/10.1371/journal.pgen.1004574