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National Institute of Environmental Health Sciences

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Publication Detail

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

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

Published In J Neurochem, (2008 Apr)

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.

PubMed ID: 17988241 Exiting the NIEHS site

MeSH Terms: Animals; Autoradiography/methods; Brain/diagnostic imaging; Brain/pathology*; Carbon Isotopes/metabolism; Carrier Proteins/metabolism; Cocaine/analogs & derivatives; Cocaine/metabolism; Disease Models, Animal; Dopamine Antagonists/metabolism; Dopamine Uptake Inhibitors/metabolism; Dopamine/metabolism*; Glial Fibrillary Acidic Protein/metabolism; Isoquinolines/metabolism; Male; Neurons/metabolism*; Papio anubis; Parkinsonian Disorders/pathology*; Positron-Emission Tomography; Raclopride/metabolism; Tetrabenazine/analogs & derivatives; Tetrabenazine/metabolism; Tyrosine 3-Monooxygenase/metabolism; Vesicular Monoamine Transport Proteins/metabolism*

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