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Sustained Increase of PKA Activity in the Postcommissural Putamen of Dyskinetic Monkeys

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Abstract

Levodopa-induced dyskinesias (LID) are a frequent complication of Parkinson’s disease pharmacotherapy that causes significant disability and narrows the therapeutic window. Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood. Here, our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication. We examined the expression and downstream activity of dopamine receptors (DR) in the striatum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropiridine (MPTP)-lesioned monkeys with and without l-DOPA treatment. Four monkeys were made dyskinetic and other four received a shorter course of l-DOPA and did not develop LID. Our results show that l-DOPA treatment induces an increase in DRD2 and DRD3 expression in the postcommissural putamen, but only DRD3 is correlated with the severity of LID. Dyskinetic monkeys show a hyperactivation of the canonical DRD1-signaling pathway, measured by an increased phosphorylation of protein kinase A (PKA) and its substrates, particularly DARPP32. In contrast, activation of the DRD2-signaling pathway, visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9, is associated with l-DOPA treatment, independently of the presence of dyskinesias. Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the DRD3 receptor and the DRD1 pathway with a sustained increase of PKA activity in the postcommissural putamen. Importantly, we found that all signaling changes related to long-term l-DOPA administration are exquisitely restricted to the postcommissural putamen, which may be related to the recurrent failure of pharmacological approaches.

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Acknowledgments

We thank Dr. Lanciego for providing control monkey brains. This study was supported by grants from the Department of Industry of the Basque Government, S-PE12UN030 (RSP) and from the Spanish Health Ministry (FIS PI08/1866 to MRL and FIS PI13/01250 to EP-N).

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Author notes

  1. Garikoitz Azkona

    Present address: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Roselló 149, 08036, Barcelona, Spain

Authors and Affiliations

  1. Animal Model Unit, Inbiomed, San Sebastian, Spain

    Garikoitz Azkona

  2. Laboratory of Stem Cells and Neural Repair, Inbiomed, P. Mikeletegi 8, 20009, San Sebastian, Spain

    Garikoitz Azkona, Rakel López de Maturana, Amaya Sousa & Rosario Sanchez-Pernaute

  3. Laboratory of Regenerative Therapy, Neuroscience Division, Centro de Investigación Médica Aplicada and Department of Neurology, Clínica Universidad de Navarra, Pamplona, 31008, Spain

    Irene Marcilla & Maria-Rosario Luquin

  4. Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Spain

    Esther Pérez-Navarro

  5. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Roselló 149, 08036, Barcelona, Spain

    Esther Pérez-Navarro

  6. Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 08036, Barcelona, Spain

    Esther Pérez-Navarro

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  1. Garikoitz Azkona
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Supplementary Figure 1

Dopamine receptor protein expression in the pre-commissural striatum. Western blot representative images (upper panel) and quantification (lower panel) of (a) DRD1, (b) DRD2 and (c) DRD3 expression in the caudate (left) and the putamen (right). Groups: Control (C; n = 3), MPTP-lesioned saline (P; n = 3), Non-dyskinetic (ND; n = 4) and Dyskinetic (D; n = 4). Data represent median and ranges. (GIF 299 kb)

High resolution image (TIFF 5,934 kb)

Supplementary Figure 2

Phosphorylation of PKA and its substrates in the postcommissural caudate. Western blot representative images (upper panel) and quantification (lower panel). (a) pSer(Thr) PKA substrates, (b) pPKAc, (c) pDARPP32, (d) pSTEP61 and (d) pERK2 levels. Groups: Control (C; n = 3), MPTP-lesioned saline (P; n = 3), Non-dyskinetic (ND; n = 4) and Dyskinetic (D; n = 4). Data represent median and ranges. (GIF 134 kb)

High resolution image (TIFF 5,113 kb)

Supplementary Figure 3

DRD2 signaling pathway in the postcommissural caudate. Western blot representative images (upper panel) and quantification (lower panel). (a) pAkt Thr308, (b) pGSK3 Tyr216 and, (c) pGSK3 Ser9 levels. Groups: Control (C; n = 3), MPTP-lesioned saline (P; n = 3), Non-dyskinetic (ND; n = 4) and Dyskinetic (D; n = 4). Data represent median and ranges. (GIF 169 kb)

(TIFF 3208 kb)

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Azkona, G., Marcilla, I., López de Maturana, R. et al. Sustained Increase of PKA Activity in the Postcommissural Putamen of Dyskinetic Monkeys. Mol Neurobiol 50, 1131–1141 (2014). https://doi.org/10.1007/s12035-014-8688-7

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