Peripheral blood a-synuclein mRNA levels are elevated in cynomolgus monkeys that chronically self-administer ethanol

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The gene SNCA (or NACP), which codes for a-synuclein, a small synaptic protein involved in dopaminergic neurotransmission, maps to
a quantitative trait locus for alcohol preference and is differentially expressed in specific brain regions in alcohol-preferring versus -nonpreferring
rats. Moreover, elevated a-synuclein messenger RNA (mRNA) and protein levels in peripheral blood have been shown to be
associated with craving in patients with alcoholism. The focus of this study was to evaluate gene expression, including the levels of a-synuclein
mRNA, in peripheral blood in nonhuman primates that were induced to drink ethanol (4 months) and then allowed 14 months of 22-
h/day access to ethanol (4% wt/vol) or water compared to alcohol-naı¨ve controls. Differential gene expression, including a-synuclein
mRNA levels, was measured in 18 cynomolgus macaque monkeys, 8 that had been chronically self-administering ethanol for 18 months
and 10 that were alcohol naı¨ve. Cynomolgus monkeys in this study self-administered ethanol at average rates of between 1.2 and 4.2 g/kg/
day. This group of ethanol-drinking monkeys had a highly significant 3.21-fold higher level of a-synuclein mRNA in peripheral blood than
alcohol-naı¨ve controls. These data agree with recent reports of elevated a-synuclein mRNA and protein in the blood of human alcoholics,
support the concept of an association between a-synuclein and alcoholism, and demonstrate, for the first time, a biomarker present in rats,
monkeys, and humans for the consumption of ethanol. 2006 Elsevier Inc. All rights reserved.

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Peripheral blood a-synuclein mRNA levels are elevated in cynomolgus
monkeys that chronically self-administer ethanol
Stephen J. Walkera,*, Kathleen A. Grantb
aIntegrative Neuroscience Initiative on Alcoholism (INIA: Stress), Department of Physiology and Pharmacology, Wake Forest
University School of Medicine, Winston-Salem, NC 27156, USA
bDepartment of Behavioral Neuroscience, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA
Received 14 February 2006; received in revised form 20 March 2006; accepted 20 March 2006
Abstract
The gene SNCA (or NACP), which codes for a-synuclein, a small synaptic protein involved in dopaminergic neurotransmission, maps to
a quantitative trait locus for alcohol preference and is differentially expressed in specific brain regions in alcohol-preferring versus -nonpreferring
rats. Moreover, elevated a-synuclein messenger RNA (mRNA) and protein levels in peripheral blood have been shown to be
associated with craving in patients with alcoholism. The focus of this study was to evaluate gene expression, including the levels of a-synuclein
mRNA, in peripheral blood in nonhuman primates that were induced to drink ethanol (4 months) and then allowed 14 months of 22-
h/day access to ethanol (4% wt/vol) or water compared to alcohol-naı¨ve controls. Differential gene expression, including a-synuclein
mRNA levels, was measured in 18 cynomolgus macaque monkeys, 8 that had been chronically self-administering ethanol for 18 months
and 10 that were alcohol naı¨ve. Cynomolgus monkeys in this study self-administered ethanol at average rates of between 1.2 and 4.2 g/kg/
day. This group of ethanol-drinking monkeys had a highly significant 3.21-fold higher level of a-synuclein mRNA in peripheral blood than
alcohol-naı¨ve controls. These data agree with recent reports of elevated a-synuclein mRNA and protein in the blood of human alcoholics,
support the concept of an association between a-synuclein and alcoholism, and demonstrate, for the first time, a biomarker present in rats,
monkeys, and humans for the consumption of ethanol. 2006 Elsevier Inc. All rights reserved.
Keywords: Alcoholism; a-Synuclein mRNA; Animal model; Self-administration; Gene expression; Blood
1. Introduction
The identification of molecular signatures of acute and
chronic alcohol consumption is a clinical and research imperative
in the alcohol field. In the clinic, these tools could
be immediately useful for diagnosing high-risk drinking, as
well as for monitoring the effects of medical treatments administered
to alcoholics. In the search for new therapeutics
for reducing/eliminating chronic alcohol consumption, targets
identified in this type of molecular profiling could be
used as objective measures of treatment efficacy. Although
there are several markers of subacute and chronic heavy
alcohol consumption currently available and in use, there
is much room for improvement given the variable and
suboptimal sensitivity and specificity of these biomarkers.
New and robust biological markers for alcohol-related
behaviors and phenotypes are needed.
One potential alcohol-related biomarker that is generating
considerable interest is a-synuclein. A number of studies
have found an association between alcohol dependence
phenotypes and a region of chromosome 4 containing
a cluster of genes that includes SNCA (synuclein, alpha;
also called NACPdnonamyloid component of plaques),
the gene coding for a-synuclein (Ehlers et al., 2004; Reich
et al., 1998; Saccone et al., 2000; Williams et al., 1999).
a-Synuclein belongs to a family of structurally related
proteins that are widely expressed in the central nervous
system and implicated in neurodegenerative pathologies,
including Parkinson’s disease (Kruger et al., 1998; Polymeropoulos
et al., 1997) and Alzheimer’s disease (Ueda
et al., 1993). Recently, the gene for a-synuclein has been
shown to map to a quantitative trait locus for alcohol preference
in rats (Liang et al., 2003). In that model, a-synuclein
messenger RNA (mRNA) and protein were expressed at significantly
higher levels (more than twofold) in specific brain
regions of inbred alcohol-preferring rats, suggesting that asynuclein
levels may contribute to alcohol preference. In
another study, involving human alcoholics and controls,
elevated circulating levels of a-synuclein mRNA were
* Corresponding author. Department of Physiology and Pharmacology,
115 S Chestnut Street, PTCRC Building,Winston-Salem, NC 27101, USA.
Tel.: 11-336-716-8556.
E-mail address: swalker@wfubmc.edu (S.J. Walker).
0741-8329/06/$ – see front matter 2006 Elsevier Inc. All rights reserved.
doi: 10.1016/j.alcohol.2006.03.008
Alcohol 38 (2006) 1–4

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