Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Westin, Jenny LU (2006)
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... (More)
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. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Parkinsons sjukdom beror på att de dopamin-producerande cellerna i hjärnan dör. Detta leder till minskad rörlighet, svårigheter i att påbörja och avsluta en rörelse, balanssvårigheter och darrningar (tremor) hos de drabbade patienterna. Varför dopamincellerna dör är oklart och i nulägat kan man inte bota Parkinsons sjukdom, men man kan lindra symptomen med mediciner. Patienterna får oftast medicinen L-DOPA som kan omvandlas till dopamin inne i hjärnan. Medcinen upptäcktes i mitten av 60-talet och revolutionerade behandlingen av sjukdomen. Patienterna återfick sin rörlighet och kunde leva ett i princip normalt liv. Tyvärr visade det sig efter några år att medicinen medförde biverkningar i form av... (More)
Popular Abstract in Swedish

Parkinsons sjukdom beror på att de dopamin-producerande cellerna i hjärnan dör. Detta leder till minskad rörlighet, svårigheter i att påbörja och avsluta en rörelse, balanssvårigheter och darrningar (tremor) hos de drabbade patienterna. Varför dopamincellerna dör är oklart och i nulägat kan man inte bota Parkinsons sjukdom, men man kan lindra symptomen med mediciner. Patienterna får oftast medicinen L-DOPA som kan omvandlas till dopamin inne i hjärnan. Medcinen upptäcktes i mitten av 60-talet och revolutionerade behandlingen av sjukdomen. Patienterna återfick sin rörlighet och kunde leva ett i princip normalt liv. Tyvärr visade det sig efter några år att medicinen medförde biverkningar i form av onormala ofrivilliga rörelser, så kallade dyskinesier. L-DOPA är fortfarande det mest använda läkemedlet mot parkinsons sjukdom, men biverkningarna utgör ett stort problem. De kan med tiden bli så allvarliga att de totalt överskuggar de positiva effekter som L-DOPA-behandlingen medför i form av ökad rörlighet. Att L-DOPA kan gå från att vara en effektiv medicin till att såsmåningom ge upphov till så svåra biverkningar är ett forskningsmässigt intressant fenomen. Det har varit svårt att kartlägga de bakomliggande molekylära mekanismerna tidigare, men nu finns finns det en råttmodell för både Parkinsonsymptomen och för de L-DOPA-framkallde dyskinesierna. Genom att selektivt förstöra dopamincellerna i ena hjärnhalvan med ett nervgift, och sedan ge råttorna en daglig injektion med L-DOPA erhålls en grupp med råttor som inte utveklar dyskinesier trots L-DOPAn (dvs de som åtnjuter fördelarna av L-DOPA men slipper biverkningarna), en grupp som blir dyskinetiska. En skala för att bedöma råttans dyskinesier enligt liknande kriterier som används för människor är framtagen. Det ger mycket goda förutsättningar för att studera uppkomsten av dyskinesier hos råttor med så kallad experimentell parkinsonism. Delarbetena i denna avhandling har gått ut på att studera förändringar på gen- och cellulär nivå, och undersöka om det finns skillader mellan råttor med dyskinesier och de råttor som inte utvecklat dyskinesier. I två av artiklarna har vi studerat en transkriptionsfaktor, dvs ett litet protein som binder sig till en annan gens DNA och gör så att denna gen blir avläst. Transkriptionsfaktorn heter FosB, och vi har sett att FosB aktiveras på nytt även efter lång tids behandling med L-DOPA hos råttor med dyskinesier. Vi har även funnit att FosB inte bryts ner i normal takt hos dyskinetiska råttor. Vi tror att denna extrema stabilitet kan ha betydelse för uppkomsten av dyskinesier. Vidare har vi gjort en screening av över 8 000 gener för att upptäcka nya, hittills okända förändringar i genuttryck mellan de dyskinetiska och de icke-dyskinetiska råttorna. Metoden kallas Microarray, och vi fann flera nya gener som verkar vara speciellt aktiva hos dyskinetiska råttor, och även en del gener som var mindre aktiva. Vi underökte även en intracellulär signalväg som kallas MAPK signalvägen och består av en kaskad av molekyler som aktiveras enligt en strikt följd för att cellens kärna ska få veta att en receptor i cellmembranet blivit aktiverad, för att se om möjligen meddelandet till cellkärnans RNA-fabrik att börja uttrycka FosB gick via denna väg. Vi fann att MAPK-vägen var aktiverad, intressant nog i långt fler celler än de som har höga nivåer av FosB. Så det är fullt möjligt att MAPK gör så att FosB börjar överuttryckas, men våra fynd tyder på att MAPK-vägen har fler uppgifter än så eftersom alla celler har aktivitet i denna signalväg. Slutligen så studerades om förekomsten av dyskinesier var kopplad till några förändringar på strukturnivå (dvs i någon av de definierade strukturer i hjärnan som består av de nervceller vi tidigare undersökt). Vi upptäckte att flera strukturer som ingår i de basala ganglierna utvecklar fler och längre blodkärl. Vad detta har för betydelse för dyskinesier och om samma typ av kärlförändringar finns i Parkinson's patienter med dyskinesier återstår att se. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Herdegen, Thomas, Institute of Pharmacology, University Hospital of Schleswig-Holstein, Kiel, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
protein synthesis, Nukleinsyror, proteinsyntes, neurofysiologi, Nucleic acids, Neurologi, neuropsykologi, L-DOPA, Dopamine, Neurology, neuropsychology, neurophysiology, Parkinson's disease
publisher
Fedreation of European Neuroscience Societies ELSEVIER
defense location
Segerfalksalen Wallenberg Neurocentrum Sölvegatan 17 22184 LUND
defense date
2006-05-24 09:15:00
ISBN
91-85481-93-9
language
English
LU publication?
yes
additional info
id
fc0bb159-b403-42ac-852f-63e5104c1231 (old id 546770)
date added to LUP
2016-04-01 15:44:45
date last changed
2018-11-21 20:36:06
@phdthesis{fc0bb159-b403-42ac-852f-63e5104c1231,
  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.},
  author       = {Westin, Jenny},
  isbn         = {91-85481-93-9},
  language     = {eng},
  publisher    = {Fedreation of European Neuroscience Societies ELSEVIER},
  school       = {Lund University},
  title        = {Intracellular signaling and cellular plasticity in a rat model of L-DOPA-induced dyskinesia},
  year         = {2006},
}