ABSTRACT
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic inclusions (Lewy bodies). Iron, which is elevated in the substantia nigra (SN) of PD patients, seems to be of pivotal importance, because of its capacity to enhance the amplification of reactive-oxygen species. Therefore, it is tempting that the iron-releasing key enzyme in heme catabolism, heme oxygenase-1 (HO-1), may represent a candidate for a genetic susceptibility to PD. In the current study, we examined a (GT)n fragment length polymorphism in the promoter region, as well as three coding SNPs in the HO-1 gene in order to assess if certain genotypes are associated with PD. Furthermore, peripheral blood expression levels of HO-1 in PD patients and healthy probands were compared. However, our analyses did not reveal a significant association of these genetic markers in the HO-1 gene with an increased susceptibility to PD.
Subject(s)
Genetic Predisposition to Disease/genetics , Heme Oxygenase-1/genetics , Parkinson Disease/enzymology , Parkinson Disease/genetics , Polymorphism, Single Nucleotide/genetics , Substantia Nigra/enzymology , Adult , Aged , Aged, 80 and over , Case-Control Studies , DNA Mutational Analysis , Exons/genetics , Female , Gene Frequency , Genetic Markers/physiology , Genetic Testing , Genotype , Heme Oxygenase-1/blood , Humans , Iron/metabolism , Iron Metabolism Disorders/complications , Iron Metabolism Disorders/enzymology , Iron Metabolism Disorders/genetics , Male , Microsatellite Repeats/genetics , Middle Aged , Parkinson Disease/physiopathology , Promoter Regions, Genetic/genetics , Substantia Nigra/physiopathologyABSTRACT
In Lewy body disease, inflammation is discussed to be involved in the pathophysiological cascade. Osteopontin (OPN) is a multifunctional molecule, which is increased in inflammatory states. Here, we analyzed the allele frequency of two SNPs of the OPN gene, serum, and CSF OPN levels in Lewy body disease patients and controls. In accordance with our previous findings, we detected increased serum (P = 0.006) and CSF OPN levels (P = 0.0003) in the Lewy body disease cohort, compared to non-Lewy body disease subjects. The genotypic variation of SNP-66 was associated with the occurrence of Lewy body disease (odds ratio: 2.64, 95% CI 1.07-6.54, unadjusted P = 0.036). SNP+1239 was not related to Lewy body disease prevalence (odds ratio 1.61, 95% CI 0.66-3.91, P = 0.29). Genotype prevalence and OPN levels were not significantly related. These findings suggest that OPN is associated with the occurrence of Lewy body disease and SNP-66 may be a susceptibility factor.
Subject(s)
Genetic Predisposition to Disease/genetics , Lewy Body Disease/genetics , Lewy Body Disease/metabolism , Osteopontin/genetics , Polymorphism, Single Nucleotide/genetics , Aged , Aged, 80 and over , DNA Mutational Analysis , Female , Gene Frequency/genetics , Genetic Markers/genetics , Genetic Testing , Genetic Variation/genetics , Genotype , Humans , Lewy Body Disease/epidemiology , Male , Middle Aged , Osteopontin/blood , Osteopontin/cerebrospinal fluid , PrevalenceABSTRACT
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic inclusions (Lewy bodies). Iron, which is elevated in the substantia nigra of PD patients, seems to be of pivotal importance, because of its capacity to enhance the amplification of reactive oxygen species. As iron enters and exits the brain via transport proteins in the blood-brain barrier (BBB), these proteins may represent candidates for a genetic susceptibility to PD. P-glycoprotein (P-gp) is one important efflux pump in the BBB. There is evidence that the function of P-gp is impaired in PD patients. In the current study we examined ten coding single nucleotide polymorphisms in the multidrug resistance gene 1 (MDR1) encoding P-gp to assess whether certain genotypes are associated with PD. However, genotyping of 300 PD patients and 302 healthy controls did not reveal a significant association between coding MDR1 gene polymorphisms and PD.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Parkinson Disease/genetics , ATP Binding Cassette Transporter, Subfamily B , Adult , Age of Onset , Aged , Aged, 80 and over , Blood-Brain Barrier/metabolism , Case-Control Studies , DNA Mutational Analysis , Europe , Female , Gene Frequency , Haplotypes , Humans , Linkage Disequilibrium , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Sex FactorsABSTRACT
A polyglutamine repeat expansion of more than 36 units in a protein called huntingtin (htt) is the only known cause of Huntington's disease (HD). The expanded repeat length is inversely correlated with the age-at-onset (AAO), however, the onset age among HD patients with CAG repeats below 60 units varies considerably. In addition to environmental factors, genetic factors different from the expanded CAG repeat length can modify the AAO of HD. We hypothezised that htt interacting proteins might contribute to this variation in the AAO and investigated human htt-associated protein-1 (HAP1) using genetic and functional assays. We identified six polymorphisms in the HAP1 gene including one that substitutes methionine (M441) for threonine (T441) at amino acid 441. Analyzing 980 European HD patients, we found that patients homozygous for the M441 genotype show an 8-year delay in the AAO. Functional assays demonstrated that human M441-HAP1 interacts with mutant htt more tightly than does human T441-HAP1, reduces soluble htt degraded products and protects against htt-mediated toxicity. We thus provide genetic and functional evidence that the M441-HAP1 polymorphism modifies the AAO of HD.
Subject(s)
Huntington Disease/epidemiology , Huntington Disease/genetics , Nerve Tissue Proteins/genetics , Polymorphism, Genetic , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Amino Acid Substitution , Child , Child, Preschool , Humans , Middle Aged , Mutation, Missense , Serotonin Plasma Membrane Transport Proteins/metabolism , Trinucleotide RepeatsABSTRACT
An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.
