The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Abeta load in brain.

Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. A -48 C/T polymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence the expression of the PS1 gene. This raises the possibility that previous conflicting findings from association studies with homozygosity for the PS1 intron 8 polymorphism might be the result of linkage disequilibrium with the -48 CC genotype. Here we provide further evidence of increased risk of AD associated with homozygosity for the -48 CC genotype (odds ratio=1.6). We also report a phenotypic correlation with Abeta(40), Abeta(42(43)), and total Abeta load in AD brains. The -48 CC genotype was associated with 47% greater total Abeta load (p<0.003) compared to CT + TT genotype bearers. These results suggest that the -48 C/T polymorphism in the PS1 promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereby influencing Abeta load.

-141 C del/ins polymorphism of the dopamine receptor 2 gene is associated with schizophrenia in a British population.

Dopamine has long been hypothesised to be involved in the pathogenesis of schizophrenia. The dopamine D2 receptor is a major site of action of neuroleptic agents used in the treatment of schizophrenia. Arinami et al. [1997; Human Mol Genet 6:577-582] have recently sequenced the dopamine receptor 2 (DRD2) gene in Japanese individuals and identified a novel polymorphism: a single cytosine deletion at position -141 disrupting a BstN1 restriction site with a frequency of 0.22 in their control group. They then found a strong association with this polymorphism and schizophrenia (p < 0.001) with an odds ratio of 0.60 in a Japanese population. We have attempted to verify their results by repeating the RFLP analysis on a sample of Scottish schizophrenics and controls. We then combined our data with those from another British sample recruited using similar procedures. The total combined sample size was 439 schizophrenics and 437 controls. We obtained a significant association--p = 0.02 with an odds ratio of 1.41. Schizophrenia is associated with the C insertion in the Japanese, but that association is reversed in Caucasians. Linkage disequilibrium with a causative polymorphism nearby is the most likely explanation for this reverse association.

Tumor suppression by manganese superoxide dismutase.

Manganese superoxide dismutase (MnSOD) is a nuclear-encoded primary antioxidant enzyme in the mitochondria. The known function of MnSOD is to remove superoxide radicals generated in the mitochondria. Given the recent explosion of evidence linking the role of MnSOD to the suppression of cancer, it has been proposed that MnSOD might function as a new type of tumor suppressor gene. Considering the role of free radicals in carcinogenesis, the significance of oxidative stress in the mitochondria, and the involvement of MnSOD in tumor suppression, the author proposes a reconciliation of the antioxidant function of MnSOD with its tumor suppression function. The focus of this report is to present some of the evidence supporting this idea.

Suppression of tumor metastasis by manganese superoxide dismutase is associated with reduced tumorigenicity and elevated fibronectin.

We have examined the tumorigenicity and the level of extracellular matrix proteins in fibrosarcoma cells expressing low (SOD-L) and high (SOD-H) MnSOD activities as well as the fibrosarcoma cells transfected with the selectable marker alone (NEO). When the cells derived from each tumor cell line were injected into syngeneic mice., the number of tumor cells required to make a tumor in one-half of the mice (TD50) was markedly increased in MnSOD-transfected cells. The decrease in the tumorigenicity of the MnSOD-transfected cells was associated with an increase in the fibronectin level. These results support the hypothesis that MnSOD is a new type of tumor-suppressor gene.

Overexpression of manganese superoxide dismutase gene changes the metastasis associated-character of the mouse fibrosarcoma, FSa-II.

The tumor metastatic ability and tumorigenicity of the mouse fibrosarcoma cell line (FSa-II) were significantly reduced due to overexpression of manganese superoxide dismutase (MnSOD) as reported previously. We investigated changes in the in vitro basic character of FSa-II cells transfected with the human MnSOD cDNA which was employed in the previous studies. FSa-II and the control vector-transfected cell line NEO, had no detectable MnSOD activity. SOD-H, into which MnSOD cDNA was transfected, is the cell line with high MnSOD activity. The malignant phenotype, characterized by serum-independence, was suppressed with elevated MnSOD activity. A quantitative comparison of transferrin receptor (TfR) by flow cytometry showed the amount of TfR on the membrane of SOD-H cells to be significantly less than that on the membrane of NEO cells. The amount of CD44 expression on SOD-H cells was almost the same as that on NEO cells. The results of this study suggest that the overexpression of MnSOD is related to suppression of the malignant phenotype and that changes of iron metabolism may play an important role in this process.

Sporadic Pick's disease in a 28-year-old woman.

Pick's disease was diagnosed in a 28-year-old woman without a family history of dementia (or other psychiatric disorder), after an initial diagnosis of functional psychosis and management with ECT and neuroleptics. The case illustrates the need for detailed neurological and cognitive testing and consideration of neurodegenerative disorders even in young patients.