Chayanon Peerapittayamongkol

Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians.

Ghosts of Selection Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency of humans, and it has been long suspected to exert an effect on Plasmodium falciparum malaria in Africa. Likewise, the increase in prevalence of the G6PD-Mahidol 487A allele among Karen people in Thailand, who only in the past few thousand years have migrated into malarious zones, may be the result of selection by Plasmodium vivax malaria. P. vivax has recently been implicated in more severe disease than previously suspected, providing both a direct selective effect through mortality and an indirect selective effect through morbidity and reproductive failure. Louicharoen et al. (p. 1546) link population-genetic evidence for positive selection in an 8-year family-based study of 3000 Karen individuals and reveal that there is an association between the presence of the G6PD-Mahidol 487A allele and a reduction in the density of P. vivax parasites circulating in the bloodstreams of infected individuals. The mutation appears to exert its effect on the physiology of immature red blood cells, which are the preferred niche for P. vivax but not of P. falciparum. Positive selection acts on a hemolytic anemia–causing mutation that affects the proliferation of a blood parasite in humans. Glucose-6-phosphate dehydrogenase (G6PD) deficiency—the most common known enzymopathy—is associated with neonatal jaundice and hemolytic anemia usually after exposure to certain infections, foods, or medications. Although G6PD-deficient alleles appear to confer a protective effect against malaria, the link with clinical protection from Plasmodium infection remains unclear. We investigated the effect of a common G6PD deficiency variant in Southeast Asia—the G6PD-Mahidol487A variant—on human survival related to vivax and falciparum malaria. Our results show that strong and recent positive selection has targeted the Mahidol variant over the past 1500 years. We found that the G6PD-Mahidol487A variant reduces vivax, but not falciparum, parasite density in humans, which indicates that Plasmodium vivax has been a driving force behind the strong selective advantage conferred by this mutation.

Protective effect of mangosteen extract against beta-amyloid-induced cytotoxicity, oxidative stress and altered proteome in SK-N-SH cells.

Beta-amyloid (A beta) plays a key role in the pathogenesis of Alzheimers disease (AD) by inducing neurotoxicity and cell death mainly through production of reactive oxygen species (ROS). Garcinia mangostana L. (mangosteen) has been recognized as a major source of natural antioxidants that could decrease ROS. However, its role in protection of A beta-induced cytotoxicity and apoptosis in neuronal cells remains unclear. We therefore examined such a protective effect of mangosteen extract (ME) by evaluating cell viability using MTT test, ROS level, caspase-3 activity, and cellular proteome. Treating SK-N-SH cells with 5-20 microM A beta((1-42)) for 24 h caused morphologically cytotoxic changes, decreased cell viability and increased ROS level, whereas preincubation with 50-400 microg/mL ME 30 min before the induction by A beta((1-42)) successfully prevented such cytotoxic effects in a dose-dependent manner (completely at 400 microg/mL). The A beta-induced increase in caspase-3 activity was also preventable by 400 microg/mL ME. Proteomic analysis using 2-D gel electrophoresis (n = 5 gels/group) followed by mass spectrometry revealed 63 proteins whose levels were significantly altered by A beta((1-42)) induction. Interestingly, changes in 10 proteins were successfully prevented by the ME pretreatment. In summary, we report herein the significant protective effects of ME against A beta-induced cytotoxicity, increased ROS, and increased caspase activity in SK-N-SH cells. Moreover, proteomic analysis revealed some proteins that might be responsible for these protective effects by ME. Further characterizations of these proteins may lead to identification of novel therapeutic targets for successful prevention and/or decreasing the severity of AD.

Association of SNP in exon 1 of HBS1L with hemoglobin F level in β0-thalassemia/hemoglobin E

Increase in fetal hemoglobin (Hb F) reduces globin chain imbalance in β-thalassemia, consequently improving symptoms. QTL mapping together with previous genome-wide association study involving approximately 110,000 gene-based SNPs in mild and severe β0-thalassemia/Hb E patients revealed SNPs in HBS1L significantly associated with severity and Hb F levels. Given its potential as binding site for transcription factor activator protein 4, HBS1L exon 1 C32T polymorphism was genotyped in 455 cases, providing for the first time evidence that C allele is associated with elevated Hb F level among β0-thalassemia/Hb E patients with XmnI-Gγ−/−and XmnI-Gγ+/−polymorphisms.

Profiling the Mitochondrial Proteome of Leber’s Hereditary Optic Neuropathy (LHON) in Thailand: Down-Regulation of Bioenergetics and Mitochondrial Protein Quality Control Pathways in Fibroblasts with the 11778G>A Mutation

Leber’s Hereditary Optic Neuropathy (LHON) is one of the commonest mitochondrial diseases. It causes total blindness, and predominantly affects young males. For the disease to develop, it is necessary for an individual to carry one of the primary mtDNA mutations 11778G>A, 14484T>C or 3460G>A. However these mutations are not sufficient to cause disease, and they do not explain the characteristic features of LHON such as the higher prevalence in males, incomplete penetrance, and relatively later age of onset. In order to explore the roles of nuclear encoded mitochondrial proteins in development of LHON, we applied a proteomic approach to samples from affected and unaffected individuals from 3 pedigrees and from 5 unrelated controls. Two-dimensional electrophoresis followed by MS/MS analysis in the mitochondrial lysate identified 17 proteins which were differentially expressed between LHON cases and unrelated controls, and 24 proteins which were differentially expressed between unaffected relatives and unrelated controls. The proteomic data were successfully validated by western blot analysis of 3 selected proteins. All of the proteins identified in the study were mitochondrial proteins and most of them were down regulated in 11778G>A mutant fibroblasts. These proteins included: subunits of OXPHOS enzyme complexes, proteins involved in intermediary metabolic processes, nucleoid related proteins, chaperones, cristae remodelling proteins and an anti-oxidant enzyme. The protein profiles of both the affected and unaffected 11778G>A carriers shared many features which differed from those of unrelated control group, revealing similar proteomic responses to 11778G>A mutation in both affected and unaffected individuals. Differentially expressed proteins revealed two broad groups: a cluster of bioenergetic pathway proteins and a cluster involved in protein quality control system. Defects in these systems are likely to impede the function of retinal ganglion cells, and may lead to the development of LHON in synergy with the primary mtDNA mutation.

The platelet amyloid precursor protein ratio as a diagnostic marker for Alzheimer’s disease in Thai patients

The platelet amyloid precursor protein (APP) ratio has recently been shown to be a promising diagnostic marker for Alzheimers disease (AD). To evaluate its usefulness in Thai patients, platelet APP was analyzed by immunoblotting. The APP ratio was calculated as the ratio of the combined band density of the 120-kD and 130-kD isoforms compared to that of the 110-kD isoform. The mean ages (and ranges) of 27 normal and 13 AD-affected subjects were 68.3 (60-84) and 79.3 (70-97) years, respectively. The Thai Mental State Examination (TMSE) scores demonstrated that the AD patients had significantly poorer cognitive functions than the normal subjects, with mean TMSE scores of 20.3 and 27.6 (maximum score of 30 points), respectively (p<0.05). The platelet APP ratios of the AD patients were significantly lower than those of normal subjects: values (mean ± standard deviation) were 7.32 ± 1.29 and 9.13 ± 3.00, respectively (p<0.05) for AD patients and normal subjects. However, the ranges of the APP ratios from both groups markedly overlapped, which precluded the establishment of a cutoff level to differentiate between the AD and normal subjects. In addition, no significant correlations were observed between the platelet APP ratio and the TMSE score or between the APP ratio and the serum cholesterol in this study, in contrast to previous reports.

Single nucleotide polymorphisms and haplotypes of protein C and protein S genes in the Thai population.

Protein C (PC) and protein S (PS) play key roles in an anticoagulant pathway in order to control the haemostatic system. We identified single nucleotide polymorphisms (SNPs) and/or haplotypes in the promotor and exons of the whole PC and PS genes and in the 3′-untranslated region of the PS gene in 55 Thai individuals. The PC gene revealed 10 haplotypes. One synonymous SNP at 2196 was found in the normal Thai population with a minor allele frequency of 4.90%. One homozygous mutation in exon 7, R147W, co-segregated with the synonymous SNP 2196 (homozygote) of the PC gene, resulting in decreased PC activity and antigenic levels. The PS gene revealed three haplotypes with two frequent dimorphisms in exon 15 and the 3′-untranslated region. The most frequent haplotype in the PS gene was H3 (wild type). There was no correlation between the haplotypes of PC and PS genes with functional and antigenic levels of PC and PS.