Mitochondrial abnormalities in the putamen in Parkinson’s disease dyskinesia
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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.
KeywordsParkinson’s disease Dyskinesia Putamen Mitochondria Respiratory chain
The authors are indebted to the staff of the Harvard Brain Tissue Resource Center at McLean Hospital, who provided all tissues and to the study subjects. Angela Cenci, MD, provided helpful discussions. Melissa Hodges provided technical support in the laboratory. This work was supported by the National Institutes of Health [NS48235 to C.K.; MH068855 to HBTRC]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutes or the National Institutes of Health.
- 3.Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B (Methodol) 57:289–300Google Scholar
- 12.Cookson MR DJ-1, PINK1, and their effects on mitochondrial pathways. Mov Disord 25(Suppl 1):S44–S48Google Scholar