Five point mutations within the amyloid beta-protein (Abeta) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer's disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Abeta production, whether or not intra-Abeta mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate. These substantial differences in aggregation together with our observation that aggregated wild type Abeta(1-40) was much less well degraded than monomeric wild type Abeta(1-40), prompted us to assess whether or not disease-associated intra-Abeta mutations alter proteolysis independent of their effects on aggregation. Neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin play a major role in Abeta catabolism, therefore we compared the ability of these enzymes to degrade wild type and mutant monomeric Abeta peptides. Experiments investigating proteolysis revealed that all monomeric peptides are degraded similarly by IDE and plasmin, but that the Flemish peptide was degraded significantly more slowly by NEP than wild type Abeta or any of the other mutant peptides. This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation.
Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.
The activity of tyrosine hydroxylase, the key enzyme in catecholamine biosynthesis, was studied along with adrenoceptor density in the brains of male CBA/Lac, BALB/cLac, and C57BL/6J mice, which show different responses to novel environments. C57BL mice showed the highest level of movement activity and the lowest level of emotionality in a novel environment. Mice of this line also showed the highest brainstem tyrosine hydroxylase activity. At the same time, the density of beta-adrenoceptors in the cortex and hypothalamus of C57BL mice was lower than in the other two lines of mice, while the density of alpha2-adrenoceptors in these parts of the brain was lower than in CBA mice. In BALB mice, movement activity was twice as high as in CBA mice, while levels of emotionality were similar in these two lines. Tyrosine hydroxylase activity was higher in the cerebral cortex of BALB mice, while the density of alpha2-adrenoceptors was lower than in CBA mice. These results show that increased investigative activity and decreased emotionality were seen in animals with higher levels of noradrenaline synthesis and decreased density of adrenergic receptors in the brain.
The human p53 tumor suppressor gene (TP53) is considered as a candidate susceptibility gene for schizophrenia because of its functions in neurodevelopment. To test for an association between TP53 and schizophrenia, both the case-control study and the transmission disequilibrium test (TDT) were performed on genotype data from eight polymorphisms in TP53. Our samples included 286 Toronto schizophrenia cases and 264 controls, and 163 Portuguese nuclear families. In the Toronto case-control study significant differences of allele frequencies of the CAA Ins/Del (p=0.027) and the 16bp Ins/Del (p=0.022) were detected. In TDT analysis we found significant differences for transmission of the CAA Ins/Del (p=0.017) in Portuguese schizophrenia families. Haplotype analysis also showed a significant association between TP53 and schizophrenia. These results provide further evidence that TP53 may play a role in the pathogenesis of schizophrenia.
Previous studies have found associations between Parkinson's disease (PD) and polymorphisms located within both the alpha-synuclein gene (SNCA) promoter and other gene regions. Our aim was to study SNCA gene markers in a closely matched Norwegian PD population to examine the genetic relationship between different polymorphisms associated with the disease.
We genotyped seven single nucleotide polymorphisms (SNPs) located in the SNCA promoter and two SNPs in the 3' gene region and seven microsatellite markers located across the gene in a closely matched series of 236 PD patients and 236 controls. Linkage disequilibrium (LD) structure was examined, and association of single markers and gene haplotypes analyzed.
Several markers located across the SNCA gene were associated with PD, including marker alleles associated with disease in previous studies (Rep1 263-bp allele, rs356165 and rs356219).
LD between associated marker alleles located across the SNCA gene suggests that a single genetic effect might explain the previous reported association in the promoter and 3' regions.
Disturbances in central serotonergic systems have been hypothesized to be involved in seasonal affective disorder (SAD). Association between SAD and the shorter allele of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR) has been reported in an American sample. We have genotyped 82 SAD patients and 82 healthy controls from Sweden, Finland, and Germany for this and five other polymorphisms in the genes coding for serotonin receptors 5-HT2A and 5-HT2C, tryptophan hydroxylase and white. No associations with SAD or seasonality (seasonal variations in mood and behavior) were detected. Although minor effects cannot be excluded, our results suggest that these polymorphisms do not play a major role in the pathogenesis of SAD in the northern European population.
Recently, association of a TOR1A(DYT1)/TOR1B risk haplotype with common forms of idiopathic dystonia has been reported in the Icelandic population. Here we report a strong association of two single nucleotide polymorphisms within or in close proximity to the TOR1A 3'UTR, with the lowest p value being 0.000008, in a larger cohort of German and Austrian patients with predominantly focal sporadic dystonia.
Autistic disorder is a neurodevelopmental disorder where genetic factors play an important role. We previously described an association between a subgroup of French autistic patients and an allele of a non-synonymous single nucleotide polymorphism (nsSNP: OMGP62 G>A or rs11080149) in the gene coding for the oligodendrocyte and myelin glycoprotein (OMG), located at 7Mb from the marker D17S250, linked to autism in two independent genome scan studies. We report a study on 431 families with 1 affected child from different origins: French Canada (n=262), Italy (n=123) and United States (n=46). We analyzed the transmission of the rs11080149 alleles from parents to their affected children. There was a preferential transmission of the G allele from parents to affected children (p=0.0017) in the overall sample. Paternal and maternal transmission rates were both skewed. Taking into account our previous results obtained in a French group of patients, where we observed an association with allele A, a direct role of this polymorphism is improbable in autism. The associations observed in Japanese and French patients, the linkage studies and the present work speak in favor of the existence of a susceptibility gene for autism in the NF1 locus.