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

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.

Mechanisms of lead and manganese neurotoxicity

“…129,130,133,134,143,254 Mn appears to interfere with dopaminergic synaptic transmission, possibly by impairing presynaptic DA release. 205,238,247,255 The developmental effects of either metal on cognition and behaviour in children may be linked to this common theme of toxicity. The developing brain is particularly sensitive to agents that disrupt synaptic activity, 256–258 as synaptic development depends critically on feedback signalling between neurons.…”

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

“…Multi-tracer PET imaging in a monkey model of PD induced by chronic MPTP treatment at a low dose shows progressive nigrostriatal dopaminergic neurodegeneration, and this results in a reduced storage capacity of VMAT2 and decreased uptake of [19] , suggesting that VMAT2 binding sites are AV-133) is a novel 18 F-labeled tetrabenazine derivative that selectively binds to VMAT2 with high affi nity [20,21] . [23] .…”

In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with 18F-AV-133

“…Previous PET studies with 11 C-DTBZ have shown decreased binding to VMAT2 in the striatum of PD patients (5,8,9). A reduction of VMAT2 reflects the degeneration of nigrostriatal dopaminergic neurons and is less susceptible than DAT to compensatory changes occurring with the loss of dopaminergic neurons (9,10). The in vivo measurement of VMAT2 density could, thus, be useful for the early and differential diagnosis of PD.…”