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Molecular basis of L-DOPA-induced dyskinesia : studies on striatal signaling

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posted on 2024-09-03, 02:01 authored by Emanuela Santini

Parkinson s disease (PD) is a neurological disorder characterized by tremor, rigidity and bradykinesia. PD is caused by selective degeneration of the dopaminergic neurons, which originate in the substantia nigra pars compacta (SNc) and project to the striatum. Parkinsonian patients are treated with L-3,4-dihydroxyphenylalanine (L-DOPA), which effectively counteracts the disease by restoring dopamine (DA) transmission in the striatum. However, the use of L-DOPA is complicated by the appearance of severe motor side effects, known as L-DOPA-induced dyskinesia (LID), which represent one of the major challenges to the existing therapy for PD. The goal of this thesis is to identify molecular mechanisms involved in LID. Work has been centered on the medium spiny neurons (MSNs) of the striatum, which are the main target of L-DOPA.

In Paper I, we examined the involvement of the DA- and cAMP-dependent phosphoprotein of 32 KDa (DARPP-32) in LID. We found that genetic inactivation of DARPP-32, which leads to attenuation of cAMP signaling in MSNs, reduced dyskinesia. We also found that, in dyskinetic mice, increased cAMP-dependent protein kinase/DARPP-32 signaling participates to the activation of the extracellular signalregulated protein kinases 1 and 2 (ERK1/2). Increased ERK1/2 phosphorylation associated with dyskinesia was paralleled by activation of mitogen- and stress-activated kinase 1 (MSK1), phosphorylation of histone H3 and increased expression of cFos. Finally, we demonstrated that inactivation of ERK1/2, achieved using SL327 (alpha-[amino[(4-aminophenyl)thio]methylene]-2 (trifluoromethyl)benzeneacetonitrile), reduced LID. These results indicate that a significant proportion of the abnormal involuntary movements developed in response to chronic L-DOPA are attributable to hyper-activation, in striatal MSNs, of a signaling pathway including phosphorylation of DARPP-32, ERK1/2, MSK1 and histone H3.

In Paper II, we identified the specific population of striatal MSNs affected by LID. For this purpose, we employed mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoters for the dopamine D1 receptor (D1R; Drd1a-EGFP mice), or the dopamine D2 receptor (D2R; Drd2-EGFP mice), which are expressed in striatonigral and striatopallidal MSNs, respectively. We found that, in the DA depleted striatum, L-DOPA increased phosphorylation of ERK1/2, MSK1 and histone H3 in striatonigral MSNs. The effect of L-DOPA was prevented by blockade of dopamine D1Rs. The same pattern of protein phosphorylation was observed, after repeated administration of L-DOPA, in dyskinetic mice.

The ERK signaling cascade can influence the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which is involved in the regulation of mRNA translation. In Paper III we investigated the involvement of the mTOR complex I (mTORC1) in PD and LID. We found that, in the DA depleted striatum, administration of L-DOPA resulted in D1R-mediated activation of mTORC1. This response occurred selectively in striatonigral MSNs and was associated with LID. Most importantly, administration of rapamycin, an inhibitor of mTORC1, reduced LID without affecting the antiparkinsonian efficacy of L-DOPA. Thus, the mTORC1 signaling cascade may represent a novel target for anti-dyskinetic therapies.

List of scientific papers

I. Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault JA, Hervé D, Greengard P, Fisone G (2007). Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci. 27(26): 6995-7005.
https://pubmed.ncbi.nlm.nih.gov/17596448

II. Santini E, Alcacer C, Cacciatore S, Heiman M, Hervé D, Greengard P, Girault JA, Valjent E, Fisone G (2009). L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice. J Neurochem. 108(3): 621-33.
https://pubmed.ncbi.nlm.nih.gov/19187092

III. Santini E, Heiman M, Greengard P, Valjent E, Fisone G (2009). Inhibition of mTOR signaling in Parkinsons disease prevents L-DOPA-induced dyskinesia. Sci Signal. 2(80): ra36.
https://pubmed.ncbi.nlm.nih.gov/19622833

History

Defence date

2009-09-18

Department

  • Department of Neuroscience

Publication year

2009

Thesis type

  • Doctoral thesis

ISBN

978-91-7409-600-2

Number of supporting papers

3

Language

  • eng

Original publication date

2009-08-28

Author name in thesis

Santini, Emanuela

Original department name

Department of Neuroscience

Place of publication

Stockholm

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