Advanced

Transcriptional dysregulation in L-DOPA-induced dyskinesia

Andersson, Malin LU (2003)
Abstract (Swedish)
Popular Abstract in Swedish

Parkinsons sjukdom karaktäriseras av en progressiv degenerering av dopamin-producerande celler. Avsaknad av dopamin resulterar i kardinalsymptomen bradykinesi (långsamma rörelser), akinesi (avsaknad av rörelser), rigiditet (muskelstelhet) samt tremor (lågfrekventa darrningar i händerna, även kallad ”pillertrillar” rörelser). Den mest framgångsrika behandlingen består av att tillföra L-DOPA, som omvandlas till dopamin i hjärnan. L-DOPA är tyvärr associerad med komplikationer som exempelvis abnorma ofrivilliga rörelser, även kallade dyskinesier. Dessa rörelser kan utvecklas till ett stort hinder i det dagliga livet och drabbar ungefär hälften av alla patienter med Parkinson efter 4-5 års... (More)
Popular Abstract in Swedish

Parkinsons sjukdom karaktäriseras av en progressiv degenerering av dopamin-producerande celler. Avsaknad av dopamin resulterar i kardinalsymptomen bradykinesi (långsamma rörelser), akinesi (avsaknad av rörelser), rigiditet (muskelstelhet) samt tremor (lågfrekventa darrningar i händerna, även kallad ”pillertrillar” rörelser). Den mest framgångsrika behandlingen består av att tillföra L-DOPA, som omvandlas till dopamin i hjärnan. L-DOPA är tyvärr associerad med komplikationer som exempelvis abnorma ofrivilliga rörelser, även kallade dyskinesier. Dessa rörelser kan utvecklas till ett stort hinder i det dagliga livet och drabbar ungefär hälften av alla patienter med Parkinson efter 4-5 års L-DOPA-behandling. En av de typiska manifestationerna av dyskinesier är att de inträffar när koncentrationen av L-DOPA är som högst, dvs. när den anti-parkinsonistiska effekten är som bäst. Detta kallas ’peak-dose dyskinesia’ och kan återskapas i en råttmodell av Parkinsons sjukdom. Denna avhandling är fokuserad på att klargöra vilka cellulära molekyler och mekanismer som kan vara den underliggande orsaken till utvecklingen av L-DOPA-inducerade dyskinesier. I vissa avseenden kan man jämföra uppkomsten av ofrivilliga rörelser med andra beteendeförändringar som kan framkallas i hjärnan av substanser som påverkar dopaminsystemet, t.ex. drogerna kokain och amfetamin. Från forskningen inom drogmissbruk har man ofta dragit slutsatsen att samma molekylära mekanismer är verksamma i hjärnan på Parkinson-patienter med abnorma ofrivilliga rörelser. Artiklarna som ligger till grund för denna avhandling visar att så inte är fallet, och att utvecklingen av de abnorma rörelserna beror helt eller delvis på en felaktig reglering av genuttryck i bestämda delar av hjärnan. I denna modell har vi kunnat förhindra uppkomsten av dyskinesier genom att blockera de proteiner som ansvarar för den felaktiga regleringen på gennivå. Genom att identifiera några av de ansvariga proteinerna visar detta arbete på avgörande markörer som kan användas i den fortsatta forskningen kring L-DOPA-inducerade dyskinesier i patienter med Parkinsons sjukdom. (Less)
Abstract
This study explores the role of transcriptional regulation important in the development of L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. In patients with Parkinson’s disease, dyskinesia is one of the most difficult complications of the DA-replacement therapy by L-DOPA. The underlying mechanisms are still unknown, but a role of abnormal striatal plasticity has been proposed. The transcription factor cyclic AMP response element-binding protein (CREB) is believed to play a key role in DA receptor-mediated gene expression and neuroplasticity. This thesis demonstrates that the requirement of CREB depends on the experimental paradigm. CREB was required for both basal and cocaine-induced gene expression of c-Fos, FosB/?FosB,... (More)
This study explores the role of transcriptional regulation important in the development of L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. In patients with Parkinson’s disease, dyskinesia is one of the most difficult complications of the DA-replacement therapy by L-DOPA. The underlying mechanisms are still unknown, but a role of abnormal striatal plasticity has been proposed. The transcription factor cyclic AMP response element-binding protein (CREB) is believed to play a key role in DA receptor-mediated gene expression and neuroplasticity. This thesis demonstrates that the requirement of CREB depends on the experimental paradigm. CREB was required for both basal and cocaine-induced gene expression of c-Fos, FosB/?FosB, and prodynorphin mRNA (PDyn). But more importantly, CREB was not required for L-DOPA to induce the same genes in the DA-denervated striatum. An analysis of DNA-protein interactions showed that the transcription factors ?FosB and JunD appeared to supersede CREB in the binding to regulatory elements of the PDyn gene. The functional significance of ?FosB and JunD was studied using an antisense approach, whereby a local reduction of either ?FosB or JunD in the striatum was obtained. Antisense-mediated knockdown of ?FosB or JunD demonstrated that these transcription factors are causally linked with both PDyn gene expression and the development of dyskinesia in the rat model of Parkinson’s disease. A comparative analysis of FosB/?FosB and JunD at both the mRNA and protein levels disclosed a remarkably similar pattern of changes after acute and chronic L-DOPA treatment. First, junD and fosB/?fosB mRNA expression was induced by acute L-DOPA administration but declined upon repeated treatment. Second, the most prominent upregulation at the protein level was seen after chronic but not acute L-DOPA treatment. This effect was clearly dissociated from the changes in gene expression and led us to propose a new model of ?FosB/JunD induction on the gene and protein level, predicting that repeated administrations of L-DOPA progressively attenuate the transcription of the fosB and junD genes, while the respective proteins accumulate over time probably due to a lack of degradation. The findings of this thesis have implications for the development of therapies that minimize the motor complications of antiparkinsonian medications. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Associate professor Fisone, Gilberto, Karolinska Institutet, Stockholm
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Clinical genetics, neurofysiologi, Neurology, neuropsychology, neurophysiology, Neurologi, neuropsykologi, CREB, jun, fos, immediate early genes, prodynorphin, striatal plasticity, Parkinson's disease, dyskinesia, Klinisk genetik
pages
128 pages
publisher
Angela Cenci Nilsson,Wallenberg Neuroscience Centre, Neurobiology Division, BMC A11, 221 84 Lund
defense location
Segerfalksalen, Wallenberg Neurocentrum, Sölvegatan 17, Lund
defense date
2003-06-06 09:30
ISBN
91-628-5722-3
language
English
LU publication?
yes
id
7c25de01-2cbb-43b8-8bc8-afb219cc478e (old id 465870)
date added to LUP
2007-08-09 13:47:54
date last changed
2016-09-19 08:45:10
@misc{7c25de01-2cbb-43b8-8bc8-afb219cc478e,
  abstract     = {This study explores the role of transcriptional regulation important in the development of L-DOPA-induced dyskinesia in a rat model of Parkinson’s disease. In patients with Parkinson’s disease, dyskinesia is one of the most difficult complications of the DA-replacement therapy by L-DOPA. The underlying mechanisms are still unknown, but a role of abnormal striatal plasticity has been proposed. The transcription factor cyclic AMP response element-binding protein (CREB) is believed to play a key role in DA receptor-mediated gene expression and neuroplasticity. This thesis demonstrates that the requirement of CREB depends on the experimental paradigm. CREB was required for both basal and cocaine-induced gene expression of c-Fos, FosB/?FosB, and prodynorphin mRNA (PDyn). But more importantly, CREB was not required for L-DOPA to induce the same genes in the DA-denervated striatum. An analysis of DNA-protein interactions showed that the transcription factors ?FosB and JunD appeared to supersede CREB in the binding to regulatory elements of the PDyn gene. The functional significance of ?FosB and JunD was studied using an antisense approach, whereby a local reduction of either ?FosB or JunD in the striatum was obtained. Antisense-mediated knockdown of ?FosB or JunD demonstrated that these transcription factors are causally linked with both PDyn gene expression and the development of dyskinesia in the rat model of Parkinson’s disease. A comparative analysis of FosB/?FosB and JunD at both the mRNA and protein levels disclosed a remarkably similar pattern of changes after acute and chronic L-DOPA treatment. First, junD and fosB/?fosB mRNA expression was induced by acute L-DOPA administration but declined upon repeated treatment. Second, the most prominent upregulation at the protein level was seen after chronic but not acute L-DOPA treatment. This effect was clearly dissociated from the changes in gene expression and led us to propose a new model of ?FosB/JunD induction on the gene and protein level, predicting that repeated administrations of L-DOPA progressively attenuate the transcription of the fosB and junD genes, while the respective proteins accumulate over time probably due to a lack of degradation. The findings of this thesis have implications for the development of therapies that minimize the motor complications of antiparkinsonian medications.},
  author       = {Andersson, Malin},
  isbn         = {91-628-5722-3},
  keyword      = {Clinical genetics,neurofysiologi,Neurology,neuropsychology,neurophysiology,Neurologi,neuropsykologi,CREB,jun,fos,immediate early genes,prodynorphin,striatal plasticity,Parkinson's disease,dyskinesia,Klinisk genetik},
  language     = {eng},
  pages        = {128},
  publisher    = {ARRAY(0x9da0c18)},
  title        = {Transcriptional dysregulation in L-DOPA-induced dyskinesia},
  year         = {2003},
}