Reduced expression of α-synuclein in alcoholic brain: influence of SNCA-Rep1 genotype.

α-Synuclein has recently been implicated in the pathophysiology of alcohol abuse due to its role in dopaminergic neurotransmission. In these studies, genetic variability in the α-synuclein gene influences its expression which may contribute to susceptibility to chronic alcohol abuse. Real-time PCR was used to quantify α-synuclein mRNA expression in autopsy samples of human dorsolateral prefrontal cortex. Because of the association between length of the α-synuclein-repeat 1 microsatellite marker and expression levels of the gene, this marker was genotyped in a Caucasian sample of 126 controls and 117 alcoholics using capillary gel electrophoresis. The allele and genotype frequencies of α-synuclein-repeat 1 marker differed significantly between alcoholics and controls. Alcoholics had greater frequencies of the shortest allele found (267 bp). The shortest allele of the α-synuclein-repeat 1 marker was associated with decreased expression of α-synuclein in prefrontal cortex. Individuals with at least one copy of the 267 bp allele were more likely to exhibit an alcohol abuse phenotype. These results suggest that individuals with the 267 bp allele may be at increased risk of developing alcoholism and that genetic variation at the α-synuclein-repeat 1 locus may influence α-synuclein expression in the prefrontal cortex.

Significant differences in gene expression of GABA receptors in peripheral blood leukocytes of migraineurs.

Migraine is a debilitating neurovascular disorder, with a substantial genetic component. The exact cause of a migraine attack is unknown; however cortical hyperexcitability is thought to play a role. As Gamma-aminobutyric Acid (GABA) is the major inhibitory neurotransmitter in the brain, malfunctioning of this system may be a cause of the hyperexcitability. To date, there has been limited research examining the gene expression or genetics of GABA receptors in relation to migraine. The aim of our study was to determine if GABA receptors play a role in migraine by investigating their gene expression using profile in migraine affected individuals and non-affected controls by Q-PCR. Gene expression of GABA(A) receptor subunit isoforms (GABRA3, GABRB3, GABRQ) and GABA(B) receptor 2 (GABBR2) was quantified in mRNA obtained from peripheral blood leukocytes from 28 migraine subjects and 22 healthy control subjects. Analysis of results showed that two of the tested genes, GABRA3 and GABBR2, were significantly down regulated in migraineurs (P=0.018; P=0.017), compared to controls. Results from the other tested genes did not show significant gene expression variation. The results indicate that there may be specific GABA receptor gene expression variation in migraine, particularly involving the GABRA3 and GABBR2 genes. This study also identifies GABRA3 and GABBR2 as potential biomarkers to select migraineurs that may be more responsive to GABA agonists with future investigations in this area warranted.

Differential expression of 14-3-3 isoforms in human alcoholic brain.

BACKGROUND: Neuropathological damage as a result of chronic alcohol abuse often results in the impairment of cognitive function. The damage is particularly marked in the frontal cortex. The 14-3-3 protein family consists of 7 proteins, ß, γ, ε, ζ, η, θ, and σ, encoded by 7 distinct genes. They are highly conserved molecular chaperones with roles in the regulation of metabolism, signal transduction, cell-cycle control, protein trafficking, and apoptosis. They may also play an important role in neurodegeneration in chronic alcoholism. METHODS: We used real-time PCR to measure the expression of 14-3-3 mRNA transcripts in both the dorsolateral prefrontal cortex and motor cortex of human brains obtained at autopsy. RESULTS: We found significantly lower 14-3-3ß, γ, and θ expression in both cortical areas of alcoholics, but no difference in 14-3-3η expression, and higher expression of 14-3-3σ in both areas. Levels of 14-3-3ζ and ε transcripts were significantly lower only in alcoholic motor cortex. CONCLUSIONS: Altered 14-3-3 expression could contribute to synaptic dysfunction and altered neurotransmission in chronic alcohol misuse by human subjects.

Association of polymorphisms in RGS4 and expression of RGS transcripts in the brains of human alcoholics.

Chronic alcoholism leads to neurotoxic effects in the central nervous system. Neuroadaptive changes in the brain may lead to tolerance to, and dependence on, alcohol as a result of alterations in synaptic complexity. G-proteins are negatively regulated by RGS proteins, which are integral to many neural pathways that include neurotransmission, hormonal responses, and chemotactic signals. These considerations, together with findings from microarray analyses of human autopsy brain, suggest that proteins involved in G-protein signalling, specifically the RGS protein family, may play an important role in the functioning of neural systems that are affected by chronic alcohol abuse. We used Real Time PCR to measure the expression of two members of the RGS family, RGS4 and RGS7, in the superior frontal gyrus and primary motor cortex from alcoholic and non-alcoholic cases. Overall, cirrhotic alcoholics had lower expression levels of RGS4 mRNA than controls and non-cirrhotic alcoholics. We also report that the four RGS4 SNPs (SNP1, 4, 7 and 18) may be associated with alcoholism in European Caucasians at the haplotype level. The haplotype T-C-G (SNP1-4-18) may exert a protective effect against alcoholism.

Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk.

BACKGROUND: Our original studies reported an association between the iron-metabolism gene HFE and risk of childhood acute lymphoblastic leukemia (ALL), and a birth weight association in ALL. Through its effect on cell proliferation, iron is involved in both fetal development and cancer. We hypothesize that HFE links higher infant birth weight with leukemia risk and that maternal HFE genotype modifies this association. PROCEDURE: Nine hundred ninety-five infants and their mothers from the North Cumbria Community Genetics Project, and 163 incident childhood ALL cases from the Newcastle Haematology Biobank were genotyped for HFE, HAMP, TFRC variants and 21 genomic control loci. Cord blood iron levels were measured in 217 control infants. RESULTS: Three HFE variants showed correlations with birth weight with a gene-dosage relationship in males (gender effect). The association was stronger in homozygotes for TFRC S142G and when the mother was positive for any HFE variant (maternal effect). The genotypes expected to increase fetal iron levels correlated with birth weight in males and their association with ALL was stronger in females who, we postulate, could not offset iron excess by increasing their weight. CONCLUSIONS: Certain materno-fetal genotype combinations that increase fetal iron exposure showed associations with higher birth weight in males and somewhat higher ALL risk in females. Gender-specific use of iron during fetal growth may lead to this dichotomy in birth weight change. Only the materno-fetal genotype combinations that increase iron levels most extremely correlated with birth weight and ALL risk in males.