title: Mitochondrial abnormalities in the putamen in Parkinson's disease dyskinesia.
abstract: Prolonged treatment of Parkinson's disease (PD) with levodopa leads to disabling side effects collectively referred to as 'dyskinesias'. We hypothesized that bioenergetic function in the putamen might play a crucial role in the development of dyskinesias. To test this hypothesis, we used post mortem samples of the human putamen and applied real time-PCR approaches and gene expression microarrays. We found that mitochondrial DNA (mtDNA) levels are decreased in patients who have developed dyskinesias, and mtDNA damage is concomitantly increased. These pathologies were not observed in PD subjects without signs of dyskinesias. The group of nuclear mRNA transcripts coding for the proteins of the mitochondrial electron transfer chain was decreased in patients with dyskinesias to a larger extent than in patients who had not developed dyskinesias. To examine whether dopamine fluctuations affect mtDNA levels in dopaminoceptive neurons, rat striatal neurons in culture were repeatedly exposed to levodopa, dopamine or their metabolites. MtDNA levels were reduced after treatment with dopamine, but not after treatment with dopamine metabolites. Levodopa led to an increase in mtDNA levels. We conclude that mitochondrial susceptibility in the putamen plays a role in the development of dyskinesias.
authors.affiliation: Department of Pharmacology and Psychiatry, Vanderbilt University, Nashville, TN, 37232-8548, USA.
authors.forename: Alipi V
authors.initials: AV
authors.lastname: Naydenov
authors.forename: Fair
authors.initials: F
authors.lastname: Vassoler
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Luksik
authors.forename: Joanna
authors.initials: J
authors.lastname: Kaczmarska
authors.forename: Christine
authors.initials: C
authors.lastname: Konradi
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D002851:Chromatography, High Pressure Liquid; D004272:DNA, Mitochondrial / Q000187:drug effects; D004298:Dopamine / Q000009:adverse effects / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000473:pathology*; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology*; D011699:Putamen / Q000187:drug effects / Q000473:pathology*; D012313:RNA / Q000187:drug effects; D000077278:RNA, Mitochondrial; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000978:Antiparkinson Agents; D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D007980:Levodopa; D012313:RNA; D004298:Dopamine