VMAT2 and dopamine neuron loss in a primate model of Parkinson's disease

Ming Kai Chen, Hiroto Kuwabara, Yun Zhou, Robert J. Adams, James R. Brašić, Jennifer L. McGlothan, Tatyana Verina, Neal C. Burton, Mohab Alexander, Anil Kumar, Dean F. Wong, Tomás R. Guilarte

Research output: Contribution to journalArticle

Abstract

We used positron emission tomography (PET) to measure the earliest change in dopaminergic synapses and glial cell markers in a chronic, low-dose MPTP non-human primate model of Parkinson's disease (PD). In vivo levels of dopamine transporters (DAT), vesicular monoamine transporter-type 2 (VMAT2), amphetamine-induced dopamine release (AMPH-DAR), D2-dopamine receptors (D2R) and translocator protein 18 kDa (TSPO) were measured longitudinally in the striatum of MPTP-treated animals. We report an early (2 months) decrease (46%) of striatal VMAT2 in asymptomatic MPTP animals that preceded changes in DAT, D2R, and AMPH-DAR and was associated with increased TSPO levels indicative of a glial response. Subsequent PET studies showed progressive loss of all pre-synaptic dopamine markers in the striatum with expression of parkinsonism. However, glial cell activation did not track disease progression. These findings indicate that decreased VMAT2 is a key pathogenic event that precedes nigrostriatal dopamine neuron degeneration. The loss of VMAT2 may result from an association with α-synuclein aggregation induced by oxidative stress. Disruption of dopamine sequestration by reducing VMAT2 is an early pathogenic event in the dopamine neuron degeneration that occurs in the MPTP non-human primate model of PD. Genetic or environmental factors that decrease VMAT2 function may be important determinants of PD.

Original languageEnglish (US)
Pages (from-to)78-90
Number of pages13
JournalJournal of Neurochemistry
Volume105
Issue number1
DOIs
StatePublished - Apr 1 2008

Keywords

  • MPTP
  • Non-human primate
  • PET
  • Parkinson's disease
  • Translocator protein 18 kDa
  • VMAT2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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  • Cite this

    Chen, M. K., Kuwabara, H., Zhou, Y., Adams, R. J., Brašić, J. R., McGlothan, J. L., Verina, T., Burton, N. C., Alexander, M., Kumar, A., Wong, D. F., & Guilarte, T. R. (2008). VMAT2 and dopamine neuron loss in a primate model of Parkinson's disease. Journal of Neurochemistry, 105(1), 78-90. https://doi.org/10.1111/j.1471-4159.2007.05108.x