Intracellular signaling and cellular plasticity in a rat model of L-DOPA-induced dyskinesia

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder where the midbrain dopaminergic neurons are lost. Presently there is no cure for PD, and the most common treatment is to replace the lost dopamine pharmacologically by administration of the dopamine precursor L-DOPA. This works very well during the initial treatment period, but unfortunately a majority of the patients develop abnormal involuntary movements, also known as dyskinesia, after several years of L-DOPA treatment. The dyskinesia may eventually become so severe that it overshadows the beneficial effects of L-DOPA treatment. The papers included in this thesis are focused on the molecular mechanisms behind dyskinesia development. Using a rat model of L-DOPA-induced dyskinesia (LID), it is possible to investigate the changes in gene and protein expression that take place in the neurons responsible for the dyskinetic behavior. First, the dopamine pathway from the midbrain to the striatum is destroyed by an injection of the neurotoxin 6-hydroxydopamine. Striatum is the place where dopamine exerts it effect, so the lesion state is equivalent to Parkinson's disease. After a few weeks the rats are treated with L-DOPA for about 14 days, and during this period most of them develop dyskinesia in response to the treatment. The first paper of this thesis demonstrates that L-DOPA is able to induce the transcription factor ?FosB for a long time after the treatment initiation. ?FosB then control the expression of the opioid neuropeptide dynorphin (PDyn) by binding to an activation site within the promoter region of the dynorphin gene. It has been thought that L-DOPA induction of FosB is a transient phenomenon, but these results demonstrate that its induction ability is not transient but persistent. The second paper investigates the stability of the ?FosB protein once it is present in the neurons. It turns out that the stability of the ?FosB protein is much longer after L-DOPA injections to parkinsonian rats than after cocaine administration to neurologically intact rats. Furthermore, the ?FosB proteins that remain in the striatum of the dyskinetic rats keep their ability to function as transcription factors for PDyn mRNA. Together these papers indicate that ?FosB may well be a key factor behind the erroneous gene induction that manifests itself as dyskinesia. In the third paper we used a screening method called microarray to identify new, unknown changes in the striatal gene expression. The results were complex, as many genes turned out to have an altered gene expression depending on whether the animals were dyskinetic, had received L-DOPA without exhibiting dyskinesia, or if they were saline-treated lesioned control rats. One intriguing discovery is the implication of an energy dysregulation, where dyskinetic animals display an increased need of ATP, yet the enzymes needed to synthesize more ATP are downregulated. The fourth study investigates a possible role for the extracellular regulated kinase (ERK) in the signal transduction that leads to dyskinesia. We examined if ERK activation could lead to the induction of ?FosB, and discovered that this may well be the case, but that the striatal distribution pattern of ERK is much broader than that of DFosB in dyskinetic rats, which indicates that ERK is most likely to have other chores than just to drive ?FosB induction. The last study expands the focus from the striatum to include all major basal ganglia nuclei. We investigated the presence of cell genesis in the basal ganglia and discovered a pronounced proliferation of endothelial cells in these nuclei. Further investigations revealed that these cells do integrate in the existing vascular system and thus leads to angiogenesis in the basal ganglia. The angiogenesis is accompanied by alterations in the blood-brain barrier permeability.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Neurobiology
Supervisors/Advisors
  • Cenci, Angela, Supervisor, External person
Award date2006 May 24
Publisher
ISBN (Print)91-85481-93-9
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-05-24
Time: 09:15
Place: Segerfalksalen Wallenberg Neurocentrum Sölvegatan 17 22184 LUND

External reviewer(s)

Name: Herdegen, Thomas
Title: professor
Affiliation: Institute of Pharmacology, University Hospital of Schleswig-Holstein, Kiel, Germany

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<div class="article_info">JE Westin, M Andersson, M Lundblad and MA Cenci. <span class="article_issue_date">2001</span>. <span class="article_title">Persistent changes in striatal gene expression induced by long-term L-DOPA treatment in a rat model of Parkinson’s disease.</span> <span class="journal_series_title">Eur J Neurosci</span>, <span class="journal_volume">vol 14</span> <span class="journal_pages">pp 1171-1176</span>.</div>
<div class="article_info">M Andersson, JE Westin and MA Cenci. <span class="article_issue_date">2003</span>. <span class="article_title">Time-course of striatal DFosB-like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment.</span> <span class="journal_series_title">Eur J Neurosci</span>, <span class="journal_volume">vol 17</span> <span class="journal_pages">pp 661-666</span>.</div>
<div class="article_info">C Konradi, JE Westin, M Carta, M Eaton, K Kuter, A Dekundy, M Lundblad and MA Cenci. <span class="article_issue_date">2004</span>. <span class="article_title">Transcriptome analysis in a rat model of L-DOPA induced dyskinesia.</span> <span class="journal_series_title">Neurobiol Dis</span>, <span class="journal_volume">vol 17</span> <span class="journal_pages">pp 219-236</span>.</div>
<div class="article_info">JE Westin, L Vercammen, C Konradi and MA Cenci. <span class="article_issue_date">2006</span>. <span class="article_title">Spatio-temporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors.</span> (submitted)</div>
<div class="article_info">JE Westin, HS Lindgren, J Gardi, J Rendel Nyengaars, P Brundin, P Mohapel and MA Cenci. <span class="article_issue_date">2006</span>. <span class="article_title">Endothelial proliferation and increased blood-brain barrier permeability in the basal ganglia in a rat model of L-DOPA-induced dyskinesia</span> (submitted)</div>

Subject classification (UKÄ)

  • Neurosciences

Free keywords

  • protein synthesis
  • Nukleinsyror
  • proteinsyntes
  • neurofysiologi
  • Nucleic acids
  • Neurologi
  • neuropsykologi
  • L-DOPA
  • Dopamine
  • Neurology
  • neuropsychology
  • neurophysiology
  • Parkinson's disease

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