6-AMINODOPAMINE-INDUCED DEGENERATION OF CATECHOLAMINE NEURONS

the effects of 6-aminodopamine on central and peripheral catecholamine neurons using fluorescence histochemical and isotope techniques have been investigated. Systematic administration of 6-aminodopamine (20 mg/kg intraveneously) produced a rapid (within 1 h) and long-lasting depletion of endogenous noradrenaline in adrenergic nerves of mouse atrium and iris with a concomitant loss of [³H]noradrenaline uptake. The effects were dosedependent. Accumulations of noradrenaline in non-terminal axons were observed histochemically, indicating that 6-aminodopamine induces neuronal damage. Desipramine completely blocked the 6-aminodopamine induced noradrenaline depletion and reduction in [³H]noradrenaline uptake, indicating that 6-aminodopamine has to be taken up by the axonal ‘membrane pump’ to produce its effects. Themonoamine oxidase inhibitor, nialamide, potentiated the effect of 6-aminodopamine on [³H]noradrenaline uptake. 6-Aminodopamine did not affect the cell bodies of the adrenergic neurons and there was a reappearance of adrenergic nerves and recovery of [³H]noradrenaline uptake. 6-Aminodopamine does not seem to pass the blood-brain barrier after systemic injection. Intraventricular injection of 6-aminodopamine in rats led to a considerable reduction in endogenous whole brain noradrenaline and [³H]noradrenaline uptake in slices from cerebral cortex and hypothalamus. Similar, but less pronounced effects were observed on dopamine neurons in the caudate nucleus. Histochemically, pronounced accumulations of transmitter were observed in the axons of the catecholamine neurons. The results obtained favour the view that 6-aminodopamine is able to produce an acute and selective degeneration of catecholamine neurons similar to that seen after the neurotoxicagent, 6-hydroxydopamine. Both compounds seemed to be approximately equally potent in their neurotoxicity, although 6-aminodopamine seemed to be more generally toxic.     

Atrial Fibrillation Associated Chromosome 4q25 Variants Are Not Associated with PITX2c Expression in Human Adult Left Atrial Appendages

Atrial Fibrillation (AF), the most common sustained arrhythmia, has a strong genetic component, but the mechanism by which common genetic variants lead to increased AF susceptibility is unknown. Genome-wide association studies (GWAS) have identified that the single nucleotide polymorphisms (SNPs) most strongly associated with AF are located on chromosome 4q25 in an intergenic region distal to the PITX2 gene. Our objective was to determine whether the AF-associated SNPs on chromosome 4q25 were associated with PITX2c expression in adult human left atrial appendages. Analysis of a lone AF GWAS identified four independent AF risk SNPs at chromosome 4q25. Human adult left atrial appendage tissue was obtained from 239 subjects of European Ancestry and used for SNP analysis of genomic DNA and determination of PITX2c RNA expression levels by quantitative PCR. Subjects were divided into three groups based on their history of AF and pre-operative rhythm. AF rhythm subjects had higher PITX2c expression than those with history of AF but in sinus rhythm. PITX2c expression was not associated with the AF risk SNPs in human adult left atrial appendages in all subjects combined or in each of the three subgroups. However, we identified seven SNPs modestly associated with PITX2c expression located in the introns of the ENPEP gene, ∼54 kb proximal to PITX2. PITX2c expression in human adult left atrial appendages is not associated with the chromosome 4q25 AF risk SNPs; thus, the mechanism by which these SNPs are associated with AF remains enigmatic.     

Haplotype analysis of common transthyretin mutations

The most frequent transthyretin (TTR) variant associated with hereditary amyloidosis is TTR Met 30, which has its major focus in Portugal, although it also occurs in many other countries. The distribution of the mutation and its occurrence in a CpG dinucleotide lead us to question the origin of the mutation and the possibility of its having originated in Portugal. In order to investigate these questions, we studied the distribution of haplotypes associated with the Met 30 mutation in families from different European countries. All the analysed Portuguese families presented the same haplotype associated with the Met 30 mutation (haplotype I). The same was found for the Swedish and Spanish families studied. However, a distinct haplotype (haplotype III) was found in three families, one Italian, one English and one Turkish. These results suggest that, although the Portuguese Met 30 carriers might have one founder, the mutation probably recurred in populations in Europe in a similar manner to that reported in Japan. In this study, we have also analysed the haplotypes associated with other TTR variants frequent in the Portuguese population.