Dominikus Bönsch

DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism

The aim of this study was to investigate whether the DNA methylation pattern within the alpha synuclein promoter region is altered in intoxicated and early abstinence patients with alcoholism undergoing alcohol withdrawal. We observed a significant increase of the alpha synuclein promoter DNA methylation in patients with alcoholism which was significantly associated with their elevated homocysteine levels. No significant differences of the promoter DNA methylation within a control gene (presenilin-1) in alcoholics and controls were found. The present results hint to a gene specific DNA promoter hypermethylation within the alpha synuclein gene. Since hypermethylation of DNA is an important epigenetic factor in the down regulation of gene expression and since alpha synuclein has been linked to craving these findings may explain the reduced value of craving under alcohol drinking conditions.

Homocysteine associated genomic DNA hypermethylation in patients with chronic alcoholism.

Summary.Higher plasma homocysteine concentrations can influence genomic DNA methylation in peripheral blood cells. In the present controlled study we observed a significant increase (10%) of genomic DNA methylation in patients with alcoholism (t = −3.16, df = 158, p = 0.002) which was significantly associated with their elevated homocysteine levels (multiple linear regression, p < 0.001). Since methylation of DNA is an important epigenetic factor in regulation of gene expression these findings may have important implications for a possible subsequent derangement of epigenetic control these patients.

Lowered DNA methyltransferase (DNMT-3b) mRNA expression is associated with genomic DNA hypermethylation in patients with chronic alcoholism

Summary.DNA methyltransferases (DNMTs) are involved within the epigenetic control of DNA methylation processes. Recently, it has been shown that the genomic DNA methylation in patients with alcoholism is increased. In the present controlled study we observed a significant decrease of mRNA expression of DNMT-3a and DNMT-3b when comparing alcoholic patients (n = 59) with healthy controls (n = 66): DNMT-3a (t = −2.38, p = 0.019), DNMT-3b (t = −2.65, p = 0.008). No significant differences were seen for DNMT-1 and Mbd-2 (Methyl-CpG-Binding-Domain protein 2) expression. Additionally, we observed a significant negative correlation between DNMT-3b expression and the blood alcohol concentration (r = −0.45, p = 0.003) which might explain the decrease of DNMT-3b mRNA expression in alcoholic patients. Using a multivariate model we observed that the increase (10%) of genomic DNA methylation in patients with alcoholism was significantly associated with their lowered DNMT-3b mRNA expression (multiple linear regression, p = 0.014). Since methylation of DNA is an important epigenetic factor in regulation of gene expression these findings may have important implications for a possible subsequent derangement of epigenetic control in these patients.

Evidence of Increased Homocysteine Levels in Alcoholism: The Franconian Alcoholism Research Studies (FARS)

BACKGROUND A limited number of investigations have studied clearly defined patients with alcoholism and blood alcohol concentrations with their correlation to plasma homocysteine values and differentiated actively drinking patients from those with early abstinence. Therefore, this power analysis-based study was undertaken to determine whether plasma homocysteine levels are evidently altered in actively drinking alcoholic patients and patients with early abstinence. METHODS Two groups of patients with an established diagnosis of alcohol dependence. For both groups, a power of 90% (alpha = 0.05) was applied. Group A comprised 144 consecutively admitted actively drinking patients with alcoholism. Group B consisted of 56 patients with alcoholism who had abstained from alcohol for 24 to 72 hr before admission to the hospital. RESULTS Plasma homocysteine levels were significantly (t test: df = 198, t = -8.6, p < 0.0001) higher at admission when comparing group A with group B. The highly increased homocysteine levels in actively drinking patients with alcoholism were based on a strong significant positive correlation with the blood alcohol concentration (multiple regression analysis, p < 0.0001). CONCLUSIONS Plasma homocysteine levels are evidently altered in actively drinking patients with alcoholism. Even though it has been described, the authors found no evidence for an increase of homocysteine levels in alcoholic patients with early abstinence. The current results emphasize the proposed pathogenetic role of increased plasma homocysteine levels in alcohol-related disorders (i.e., brain atrophy, alcohol withdrawal seizures).

Homocysteine as a neurotoxin in chronic alcoholism.

There is evidence from in vitro and in vivo studies that homocysteine induces neuronal damage and cell loss by both excitotoxicity and different apoptotic processes. Clinical evidence suggest a strong relationship between higher plasma homocysteine levels and brain atrophy in healthy elderly subjects as well as in elderly at risk of and with Alzheimers disease. Chronic alcoholism leads to elevated plasma homocysteine levels, as shown by clinical investigations and animal experiments. In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of alcoholism-associated brain atrophy. Furthermore, taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anticonvulsive therapy could prevent this severe complication. Homocysteine plays a role in a shared biochemical cascade involving overstimulation of N-methyl-D-aspartate (NMDA) receptors, oxidative stress, activation of caspases, DNA damage, endoplasmic reticulum and mitochondrial dysfunction. These mechanisms are believed to be important in the pathogenesis of both excitotoxicity and apoptotic neurotoxicity. Prospective intervention studies may show whether the incidence of complications of alcohol withdrawal or alcoholism-associated disorders can be reduced by therapeutic measures with early lowering of elevated homocysteine levels (e.g. folate administration). The most important pathophysiological and pathobiochemical features of glutamatergic neurotransmission and of ethanol-induced hyperhomocysteinaemia are reviewed in relation to their excitotoxic and apoptotic potential.

Elevated alpha synuclein mRNA levels are associated with craving in patients with alcoholism.

BACKGROUND Alpha synuclein has been found elevated in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. METHODS The alpha synuclein mRNA expression level was measured by quantitative polymerase chain reaction in the blood of 75 male alcoholics and 69 nondrinking healthy control subjects. Alcohol craving was assessed by the Obsessive-Compulsive Drinking Scale total score, including subscales for obsessive and compulsive craving. RESULTS The alpha synuclein expression in patients with alcoholism (2.79 DeltaCT; SD = 1.69; p = .021) was significantly higher when compared with healthy control subjects (2.20 DeltaCT; SD = 1.59). Increased alpha synuclein levels significantly predict Obsessive-Compulsive Drinking Scale total score (odds ratio = 1.44, 95% confidence interval: 1.01-2.06, p = .042) and especially Obsessive-Compulsive Drinking Scale obsessive subscale (odds ratio = 1.74, 95% confidence interval: 1.18-2.58, p = .005) but not Obsessive-Compulsive Drinking Scale compulsive subscale alcohol craving. CONCLUSIONS Higher levels of alpha synuclein are associated with an increase in alcohol craving. The present results provide a novel pathophysiological approach to the explanation of craving mechanisms.

Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa

Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa

α‐Synuclein Protein Levels Are Increased in Alcoholic Patients and Are Linked to Craving

BACKGROUND Alpha synuclein has been found to be increased in dopamine neurones of cocaine abusers and in rats whose alcohol preference is inbred. Furthermore, increased alpha-synuclein messenger RNA expression has been linked to craving in patients with alcoholism. The aim of the current study was to investigate whether protein levels of alpha synuclein in alcoholics are changed and possibly influence alcohol craving. METHODS The alpha-synuclein protein expression level was measured by enzyme-linked immunosorbent assay in the serum of 49 male alcoholics and 50 nondrinking healthy controls. Alcohol craving was assessed by the Obsessive-Compulsive Drinking Scale total score, including subscales for obsessive and compulsive craving. RESULTS Alpha-synuclein protein expression in patients with alcoholism (14.33 ng/ml; SD, 13.01 ng/ml) was significantly higher (t test, T = 3.66, p < 0.0001) when compared with that of healthy controls (5.92 ng/ml; SD, 9.72 ng/ml). Using a multivariate analysis, all craving scores (Obsessive-Compulsive Drinking Scale total score and obsessive and compulsive subscale scores) in alcoholics were significantly associated with their alpha-synuclein protein levels (multiple linear regression, p < 0.014). CONCLUSIONS To our knowledge, this is the first study evaluating alpha-synuclein protein expression in alcoholics. The current study provides further evidence of altered alpha-synuclein levels in patients with alcoholism and their linkage to alcohol craving. Because alpha synuclein is involved in the modulation of dopaminergic neurotransmission, these results deliver further pathophysiological explanations of craving mechanisms.

Serum levels of BDNF are associated with craving in opiate-dependent patients

Preclinical study results suggest that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are involved in the modulation of addictive behaviour. We investigated alterations in serum levels of BDNF and GDNF in opiate-dependent patients (28 males) who received diacetylmorphine treatment within a structured opiate maintenance programme. BDNF (T = 2.735, p = 0.009) serum levels were significantly increased in the opiate-dependent patients as compared with healthy controls (21 males), whereas GDNF serum levels (T = 1.425, p = 0.162) did not differ significantly from GDNF serum levels of the healthy controls. BDNF serum levels were significantly associated with craving for heroin (measured by the Heroin Craving Questionnaire (r = 0.420, p = 0.029) and by the General Craving Scale (r = 0.457, p = 0.016), whereas GDNF serum levels were not associated with psychometric dimensions of heroin craving. In conclusion, our results show a positive association between BDNF serum levels and opiate craving in opiate-dependent patients.

Methylation matters? Decreased methylation status of genomic DNA in the blood of schizophrenic twins

Studies of schizophrenia inheritance in identical twins show a concordance of about 50%, which supports an epigenetic model. In our present study we investigated methylation of genomic DNA and promoter methylation of Reelin and SOX10 genes in peripheral blood of twins suffering from schizophrenia. Global DNA methylation was reduced (52.3%) in schizophrenic twins if compared with healthy control twins (65.7%). The reduced methylation was significant in males only. We also found a similar hypomethylation in the non-affected twins of discordant pairs and a mixed group of psychiatric controls. In discordant twins there was a relative hypermethylation of the SOX10 promoter. Within-pair-difference of methylation of Reelin promoter was significantly lower in monozygotic twins than in dizygotic twins.