Vesicular integrity in Parkinson's disease

Abstract

The defining motor characteristics of Parkinson's disease (PD) are mediated by the neurotransmitter dopamine (DA). Dopamine molecules spend most of their lifespan stored in intracellular vesicles awaiting release and very little time in the extracellular space or the cytosol. Without proper packaging of transmitter and trafficking of vesicles to the active zone, dopamine neurotransmission cannot occur. In the cytosol, dopamine is readily oxidized; excessive cytosolic dopamine oxidation may be pathogenic to nigral neurons in PD. Thus, factors that disrupt vesicular function may impair signaling and increase the vulnerability of dopamine neurons. This review outlines the many mechanisms by which disruption of vesicular function may contribute to the pathogenesis of PD. From direct inhibition of dopamine transport into vesicles by pharmacological or toxicological agents to alterations in vesicle trafficking by PD-related gene products, variations in the proper compartmentalization of dopamine can wreak havoc on a functional dopamine pathway. Findings from patient populations, imaging studies, transgenic models, and mechanistic studies will be presented to document the relationship between impaired vesicular function and vulnerability of the nigrostriatal dopamine system. Given the deleterious effects of impaired vesicular function, strategies aimed at enhancing vesicular function may be beneficial in the treatment of PD.

Fig. 1

Mechanisms of vesicular disruption in Parkinson’s disease. After synthesis, dopamine is transported into vesicles. Cytoplasmic dopamine can be oxidized; in excess, this can lead to cellular injury. a, Vesicles in the readily releasable pool dock at the presynaptic membrane. In response to an action potential and calcium influx, vesicle membranes fuse to the plasma membrane and release their contents into the synaptic space. Dopamine is then reclaimed by the dopamine transporter (DAT) and then subsequently repackaged into the vesicle. b, Pharmacological inhibition of VMAT2 prevents uptake of dopamine leading to a depleted vesicle and reduced release. c, Genetic reduction of VMAT2 expression via promoter polymorphisms in humans or genetic manipulation in mice (upper vesicle) or VMAT2 function as noted in [•] (lower vesicle) causes a reduction in vesicular filling and subsequent release. d, α-synuclein can form pores in the vesicle and cause depletion of dopamine from the vesicle or interact with cytoplasmic dopamine to form toxic species. e, Altered trafficking of the vesicle to the presynaptic membrane has been proposed to occur in the presence of overabundant α-synuclein or mutated LRRK2