VMAT2 and dopamine neuron loss in a primate model of Parkinson’s disease
Article first published online: 6 NOV 2007
© 2007 The Authors
Journal of Neurochemistry
Volume 105, Issue 1, pages 78–90, April 2008
How to Cite
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. and Guilarte, T. R. (2008), VMAT2 and dopamine neuron loss in a primate model of Parkinson’s disease. Journal of Neurochemistry, 105: 78–90. doi: 10.1111/j.1471-4159.2007.05108.x
- Issue published online: 6 NOV 2007
- Article first published online: 6 NOV 2007
- Received September 7, 2007; revised manuscript received October 9, 2007; accepted October 27, 2007.
- non-human primate;
- Parkinson’s disease;
- translocator protein 18 kDa;
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.