Original Paper

Acta Neuropathologica

, Volume 120, Issue 5, pp 623-631

Mitochondrial abnormalities in the putamen in Parkinson’s disease dyskinesia

  • Alipi V. NaydenovAffiliated withDepartment of Pharmacology and Psychiatry, Vanderbilt University
  • , Fair VassolerAffiliated withDepartment of Pharmacology and Psychiatry, Vanderbilt University
  • , Andrew S. LuksikAffiliated withDepartment of Pharmacology and Psychiatry, Vanderbilt University
  • , Joanna KaczmarskaAffiliated withDepartment of Pharmacology and Psychiatry, Vanderbilt University
  • , Christine KonradiAffiliated withDepartment of Pharmacology and Psychiatry, Vanderbilt UniversityCenter for Molecular Neuroscience, Vanderbilt UniversityKennedy Center for Research on Human Development, Vanderbilt University Email author 

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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.

Keywords

Parkinson’s disease Dyskinesia Putamen Mitochondria Respiratory chain