Vesicular neurotransmitter transporters in Huntington's disease: Initial observations and comparison with traditional synaptic markers

Abstract

Markers of identified neuronal populations have previously suggested selective degeneration of projection neurons in Huntington's disease (HD) striatum. Interpretations are, however, limited by effects of compensatory regulation and atrophy. Studies of the vesicular monoamine transporter type-2 (VMAT2) and of the vesicular acetylcholine transporter (VAChT) in experimental animals indicate that they are robust markers of presynaptic integrity and are not subject to regulation. We measured dopamine and acetylcholine vesicular transporters to characterize the selectivity of degeneration in HD striatum. Brains were obtained at autopsy from four HD patients and five controls. Autoradiography was used to quantify radioligand binding to VMAT2, VAChT, the dopamine plasmalemmal transporter (DAT), benzodiazepine (BZ) binding sites, and D2-type dopamine receptors. The activity of choline acetyltransferase (ChAT) was determined as an additional marker of cholinergic neurons. Autoradiograms were analyzed by video-assisted densitometry and assessment of atrophy was made from regional structural areas in the coronal projection. Striatal VMAT2, DAT, and VAChT concentrations were unchanged or increased, while D2 and BZ binding and ChAT activity were decreased in HD. After atrophy correction, all striatal binding sites were decreased. However, the decrease in ChAT activity was 3-fold greater than that of VAChT binding. In addition to degeneration of striatal projection neurons, there are losses of extrinsic nigrostriatal projections and of striatal cholinergic interneurons in HD on the basis of vesicular transporter measures. There is also markedly reduced expression of ChAT by surviving cholinergic striatal interneurons.

Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease

“…Additional biochemical analysis revealed progressive loss of striatal D 1 and D 2 receptors in postmortem HD brains (Joyce et al, 1988;Filloux et al, 1990;Richfield et al, 1991;Glass et al, 2000;Suzuki et al, 2001). Imaging studies also reported reduction of striatal D 1 and D 2 receptors in HD patients (Sedvall et al, 1994;Turjanski et al, 1995) and asymptomatic HD mutation carriers (Antonini et al, 1996;Weeks et al, 1996;Ginovart et al, 1997).…”

Kinesin‐2 differentially regulates the anterograde axonal transports of acetylcholinesterase and choline acetyltransferase in Drosophila

“…Genetic and pharmacological studies showed that block in ChAT, AChE, or VAChT activity by either mutations or antagonist treatments causes synaptic malfunctioning and paralysis in worms, insects, and humans (Engel et al, 1999;Kitamoto et al, 2000;Ohno et al, 2001;Suzuki et al, 2001). Experimental evidence also indicates that relative neuronal levels of these three enzymes are actively coregulated.…”

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

“…Furthermore, reserpine and TBZ deplete both DA-and serotonin-containing vesicles, leading to symptoms including gastrointestinal distress, depression, and fatigue. Radiolabeled TBZ and related derivatives with high affinity for VMAT2 are used as imaging tools, especially in relation to diagnosis and understanding of several disease states, such as PD, Huntington's disease, bipolar disorder, and schizophrenia (Zubieta et al, 2000(Zubieta et al, , 2001Frey et al, 2001;Suzuki et al, 2001;Bohnen et al, 2006). TBZ is approved by the U.S. Food and Drug Administration for symptomatic treatment of Huntington's disease, which is characterized, in part, by dysregulation of dopaminergic neurotransmission (Frank and Jankovic, 2010).…”