α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats

Liang, Tiebing; Spence, John P.; Liu, Lixiang; Strother, Wendy N.; Chang, Hwai Wen; Ellison, Julie A.; Lumeng, Lawrence; Li, Ting Kai; Foroud, Tatiana; Carr, Lucinda G.

doi:10.1073/pnas.0737182100

Cited by 116 publications

(136 citation statements)

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“…Using a family based test of association in multiplex alcoholic pedigrees, analyses in the 3′ end of SNCA identified a haplotype overestimated in European-American individuals who crave alcohol and a different haplotype, which was preferentially transmitted to noncravers (Foroud et al 2007). These observations are consistent with a previous report in alcohol preferring P rats, which proposed that SNPs in the 3′UTR of Snca contribute to alcohol preference (Liang et al, 2003). However, a more exhaustive analysis in two American Indian populations failed to find an association of alpha synuclein with alcohol and drug dependence (Clarimon et al, 2007).…”

Section: Discussionsupporting

confidence: 92%

“…Alpha synuclein is elevated in rats whose alcohol preference is inbred (Liang et al, 2003) and high levels are associated with an increase in alcohol craving in patients during withdrawal (Bonsch et al, 2005a;Bonsch et al, 2004). Peripheral blood alpha synuclein mRNA levels are elevated in cynomolgus monkeys that chronically self-administer ethanol (Walker and Grant, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Alpha synuclein protein levels are increased in serum from recently abstinent cocaine abusers

Mash

Adi

Duque

et al. 2008

Drug and Alcohol Dependence

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Alpha synuclein is increased in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. Recent studies have shown increased alpha-synuclein protein expression in serum of alcoholic patients that is linked with severity of alcohol craving. The aim of this study was to analyze the serum levels of alpha synuclein in healthy subjects and in recently abstinent cocaine abusers. Alpha synuclein protein expression was measured by enzyme-linked immunosorbent assay in serum specimens obtained from 38 recently abstinent cocaine dependent patients and 14 control subjects. The presence of cocaine dependence disorder was based on the Structured Clinical Interview (DSM-IV). Drug severity was assessed by the Addiction Severity Index ratings and composite measures. Scores of the intensity and frequency of cocaine craving episodes were obtained from the Minnesota Cocaine Craving Questionnaire. The serum concentrations of alpha synuclein in cocaine dependent patients were significantly higher as compared with age-matched drug-free controls (p < 0.001). Alpha synuclein levels in blood were significantly correlated with the intensity (r = 0.60, p < 0.001) and frequency (r = 0.64. p < 0.001) of cocaine craving and with thirty days of cocaine use in the prior month before entry to treatment (r = 0.56, p < 0.005). However, there was no correlation between the serum protein levels of alpha synuclein and age in either group. This report is the first demonstration of altered alpha synuclein levels in peripheral blood from cocaine abusers. These data agree with previous reports in postmortem brain of cocaine abusers and provide support for an association between alpha synuclein and cocaine dependence.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Alpha synuclein protein levels are increased in serum from recently abstinent cocaine abusers

Mash

Adi

Duque

et al. 2008

Drug and Alcohol Dependence

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“…Complementary methods, quantitative trait locus (QTL) analysis, and total gene expression analysis (TOGA; a registered trademark of Digital Gene Technologies) were conducted to identify genes that influence alcohol consumption in iP and iNP rats (Liang et al, 2003). A genome screen of the iP × iNP F2 animals identified QTLs on rat chromosomes 3, 4, and 8 Carr et al, 1998).…”

Section: Hhs Public Accessmentioning

confidence: 99%

“…In these lines, P rats display the phenotypic characteristics considered necessary for an animal model of alcoholism (Cicero, 1979). Subsequently, inbred P (iP) and NP (iNP) strains that have maintained highly discordant alcohol consumption scores were established.Complementary methods, quantitative trait locus (QTL) analysis, and total gene expression analysis (TOGA; a registered trademark of Digital Gene Technologies) were conducted to identify genes that influence alcohol consumption in iP and iNP rats (Liang et al, 2003). A genome screen of the iP × iNP F2 animals identified QTLs on rat chromosomes 3, 4, and 8 Carr et al, 1998).…”

mentioning

confidence: 99%

“…Animal models of alcohol preference have been used to identify both chromosomal loci and candidate genes that may influence alcohol-drinking behavior Foroud et al, 2000;Grisel et al, 2002;Liang et al, 2003). The alcohol-preferring (P) andnonpreferring (NP) rat lines were developed through bidirectional selective breeding from a randomly bred closed colony of Wistar rats [Wrm: WRC(WI)BR] on the basis of alcohol consumption and preference (Li et al, 1991).…”

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Glutathione S‐Transferase 8‐8 Expression Is Lower in Alcohol‐Preferring Than in Alcohol‐Nonpreferring Rats

Liang

Habegger

Spence

et al. 2004

Alcoholism Clin & Exp Res

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Objective-A primary focus of alcohol research is to provide novel targets for alcohol treatment by identifying genes that predispose individuals to drink alcohol. Animal models of alcoholism developed by selective breeding are invaluable tools to elucidate both the genetic nature and the underlying biological mechanisms that contribute to alcohol dependence. These selected lines (high alcohol preferring and low alcohol preferring) display phenotypic and genetic differences that can be studied to further our understanding of alcohol preference and related genetic traits. By combining molecular techniques, genetic and physiological factors that underlie the cause of alcoholism can be identified.Methods-Total gene expression analysis was used to identify genes that are differentially expressed in specific brain regions between alcohol-naïve, inbred alcohol-preferring (iP) andnonpreferring (iNP) rats. Quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot, and sequence analysis were used to further characterize rat glutathione S-transferase .Results-Lower expression of rGST 8-8 mRNA was observed in discrete brain regions of iP compared with iNP animals, and these expression differences were confirmed. To determine additional expression patterns of rGST 8-8, we used in situ hybridization. Rat GST 8-8 was highly expressed in hippocampus, the choroid plexus of the dorsal third ventricle and the lateral ventricle, and ependymal cells along the dorsal third ventricle and the third ventricle. Western blot analysis showed that rGST 8-8 protein levels were lower in the hippocampus and the amygdala of iP compared with iNP. A silent single-nucleotide polymorphism in the coding region and three single-nucleotide polymorphisms in the 3′-UTR were identified in the rGST 8-8 cDNA.Conclusion-There is regional variation of rGST 8-8 expression in the brain, at both the mRNA and protein level, and the iP strain has lower innate rGST 8-8 levels than the iNP strain in discrete brain regions. Alcoholism is a complex disorder influenced by both environmental and genetic factors. The genetic contribution to alcoholism likely results from the action of multiple, possibly interacting genes. Identification of the genes that influence alcohol drinking is an important area of research in the alcohol field and has involved several strategies, including the use of human studies and the development of genetic animal models of alcoholism. Sequencing of the rat genome has revealed that most human genes have counterparts in the rat (Rat Genome Sequencing Project Consortium, 2004). Thus, identification of interesting genes in a rat model can provide candidate genes for specific diseases that can be evaluated further in humans. HHS Public AccessAnimal models of alcohol preference have been used to identify both chromosomal loci and candidate genes that may influence alcohol-drinking behavior Foroud et al., 2000;Grisel et al., 2002;Liang et al., 2003). The alcohol-preferring (P) andnonpreferring (NP) ...

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Multiple regions of α‐synuclein are associated with Parkinson's disease

Mueller¹,

Fuchs

Höfer

et al. 2005

Annals of Neurology

224

148

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alpha-Synuclein is considered to play an important role in the pathogenesis of both the rare familial and the common sporadic forms of Parkinson's disease. Previous reports primarily have tested the association of alpha-synuclein promoter polymorphisms with idiopathic Parkinson's disease, but results are controversial. We first characterized the linkage disequilibrium structure of the alpha-synuclein gene region with a dense set of 56 genetic markers and subsequently performed two independent case-control association analyses using tagging markers. We could distinguish two large linkage disequilibrium blocks spanning the alpha-synuclein gene. Several markers within the 3'-block around exons 5 and 6 showed strong association with Parkinson's disease (p = 0.00009). Effects of the associated variants might be mediated by regulatory elements in this highly conserved region or by a frequency shift in a previously described splice variant lacking exon 5. A direct association with promoter polymorphisms could not be replicated in our sample set. A second set of markers in the 5'-block of the gene were also significantly associated with Parkinson's disease, when young patients and female subjects were analyzed separately. These findings indicate locus heterogeneity for the pathogenesis of Parkinson's disease in different genetic or physiological environments, related to sex and age.

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α-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats

Cited by 116 publications

References 42 publications

Alpha synuclein protein levels are increased in serum from recently abstinent cocaine abusers

Alpha synuclein protein levels are increased in serum from recently abstinent cocaine abusers

Glutathione S‐Transferase 8‐8 Expression Is Lower in Alcohol‐Preferring Than in Alcohol‐Nonpreferring Rats

Multiple regions of α‐synuclein are associated with Parkinson's disease

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