VMAT2 and dopamine neuron loss in a primate model of Parkinson's disease.
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.
Chen
Ming-Kai
MK
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
Kuwabara
Hiroto
H
Zhou
Yun
Y
Adams
Robert J
RJ
Brasić
James R
JR
McGlothan
Jennifer L
JL
Verina
Tatyana
T
Burton
Neal C
NC
Alexander
Mohab
M
Kumar
Anil
A
Wong
Dean F
DF
Guilarte
Tomás R
TR
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D002247:Carbon Isotopes / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism*; D048530:Papio anubis; D020734:Parkinsonian Disorders / Q000473:pathology*; D049268:Positron-Emission Tomography; D020891:Raclopride / Q000378:metabolism; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D002247:Carbon Isotopes; D002352:Carrier Proteins; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007546:Isoquinolines; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D020891:Raclopride; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine; C037850:PK 11195; D013747:Tetrabenazine