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.

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

“…Furthermore, in mice, reduced VMAT2 function produces dopamine-mediated toxicity and neurodegeneration in the nigrostriatal dopamine system, and restoration of VMAT2 function may be an important intervention in the treatment of PD (41)(42)(43)(44). Therefore, impaired vesicular packaging of dopamine may represent a common pathological mechanism of PD (45).…”

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

“…Given the vast scope of the field, only selected mechanisms and disorders are discussed herein. These are not all encompassing, and the reader is referred to additional recent reviews (Sulzer et al, 2005;Alter et al, 2013;Schmitt et al, 2013;Vaughan and Foster, 2013;Howell and Negus, 2014;Nickell et al, 2014).…”

Immunochemical localization of vesicular monoamine transporter 2 (VMAT2) in mouse brain

“…VMAT2 utilizes an electrochemical gradient maintained by a vesicular H + -ATPase to transport one monoamine molecule (dopamine, serotonin, norepinephrine, or histamine) into the highly acidic vesicular lumen in exchange for the efflux of two protons (Chaudhry et al, 2008; Eiden et al, 2004; Erickson et al, 1995; Wimalasena, 2011). The function of VMAT2 is multifold: it prepares neurotransmitters for presynaptic release (Erickson et al, 1992; Henry et al, 1994) and prevents oxidative damage by sequestering deleterious cytosolic monoamines into the vesicle (Alter et al, 2013; Sulzer and Zecca, 2000). …”