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Mitochondrial abnormalities in the putamen in Parkinson’s disease dyskinesia

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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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Pharmacology and Psychiatry, Vanderbilt University, MRB 3, Room 8160, 465 21st Avenue South, Nashville, TN, 37232-8548, USA

    Alipi V. Naydenov, Fair Vassoler, Andrew S. Luksik, Joanna Kaczmarska & Christine Konradi

  2. Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN, 37232, USA

    Christine Konradi

  3. Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, 37203, USA

    Christine Konradi

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  1. Alipi V. Naydenov
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  2. Fair Vassoler
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  3. Andrew S. Luksik
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  4. Joanna Kaczmarska
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  5. Christine Konradi
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Corresponding author

Correspondence to Christine Konradi.

Electronic supplementary material

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401_2010_740_MOESM1_ESM.doc

Demographic data of all samples. Not all samples were available for each experiment. Duration of disease and L-dopa levels were significantly different in the entire group. Thus, subgroups of samples were used which were controlled for these parameters. (DOC 121 kb)

Sequences of primer pairs for PCR reactions (DOC 79 kb)

401_2010_740_MOESM3_ESM.doc

Detailed gene expression data of electron transport proteins. ‘Mean’ data are natural values; p-values were obtained from log2 –transformed data to ensure normal distribution. (DOC 131 kb)

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Naydenov, A.V., Vassoler, F., Luksik, A.S. et al. Mitochondrial abnormalities in the putamen in Parkinson’s disease dyskinesia. Acta Neuropathol 120, 623–631 (2010). https://doi.org/10.1007/s00401-010-0740-8

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  • DOI: https://doi.org/10.1007/s00401-010-0740-8

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