| 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 alpha-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. |
| Authors | Ming-Kai Chen, Hiroto Kuwabara, Yun Zhou, Robert J Adams, James R Brasić, Jennifer L McGlothan, Tatyana Verina, Neal C Burton, Mohab Alexander, Anil Kumar, Dean F Wong, Tomás R Guilarte
(Affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.)
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| Journal | Journal of neurochemistry
(J Neurochem)
Vol. 105
Issue 1
Pg. 78-90
(Apr 2008)
ISSN: 1471-4159 England |
| PMID | 17988241
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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| Chemical References |
- Carbon Isotopes
- Carrier Proteins
- Dopamine Antagonists
- Dopamine Uptake Inhibitors
- Glial Fibrillary Acidic Protein
- Isoquinolines
- Vesicular Monoamine Transport Proteins
- dihydrotetrabenazine
- Cocaine
- (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
- Dopamine
- Tetrabenazine
- Raclopride
- PK 11195
- Tyrosine 3-Monooxygenase
|
| Topics |
- Animals
- Autoradiography
(methods)
- Brain
(pathology, radionuclide imaging)
- Carbon Isotopes
(metabolism)
- Carrier Proteins
(metabolism)
- Cocaine
(analogs & derivatives, metabolism)
- Disease Models, Animal
- Dopamine
(metabolism)
- Dopamine Antagonists
(metabolism)
- Dopamine Uptake Inhibitors
(metabolism)
- Glial Fibrillary Acidic Protein
(metabolism)
- Isoquinolines
(metabolism)
- Male
- Neurons
(metabolism)
- Papio anubis
- Parkinsonian Disorders
(pathology)
- Positron-Emission Tomography
- Raclopride
(metabolism)
- Tetrabenazine
(analogs & derivatives, metabolism)
- Tyrosine 3-Monooxygenase
(metabolism)
- Vesicular Monoamine Transport Proteins
(metabolism)
|
