PGC-1alpha as modifier of onset age in Huntington disease

Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestations despite similar CAG repeat lengths. This has led to a search for genetic factors that influence AO. In order to identify such a genetic modifier, we analysed polymorphisms in the PGC-1alpha gene. Recent data indicate inhibition of PGC-1alpha function by mutant Htt supporting a link between transcriptional deregulation and mitochondrial dysfunction in HD. In > 400 HD patients, a polymorphism located within intron 2, a potential recombination hot spot, explains a small, but statistically significant, amount of the variability in AO. Our data suggest that PGC-1alpha has modifying effects on the pathogenic process in HD

Failure to confirm influence of Methyltetrahydrofolate reductase (MTHFR) polymorphisms on age at onset of Huntington disease

BACKGROUND: Huntington disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Recently, suggestive association has been reported between a single nucleotide polymorphism (SNP; rs1801131, also known as A1298C) in the methyltetrahydrofolate reductase (MTHFR) gene and AO of HD. 5,10-MTHFR is a key enzyme in the folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using part of a previously established study cohort plus additional patients and appropriate statistical methods, we reinvestigated two polymorphisms in the MTHFR gene, C677T and A1298C, as well as their association with AO in 167 HD patients. RESULTS: There was no statistically significant impact on AO for HD patients, neither of MTHFR SNPs nor of the combinations thereof. CONCLUSION: Contrary to previously described evidence the A1298C polymorphism in the MTHFR gene does not appear to modulate AO of HD patients

No association between polymorphisms in the BDNF gene and age at onset in Huntington disease

BACKGROUND: Recent evidence suggests that brain-derived neurotrophic factor (BDNF) is an attractive candidate for modifying age at onset (AO) in Huntington disease (HD). In particular, the functional Val66Met polymorphism appeared to exert a significant effect. Here we evaluate BDNF variability with respect to AO of HD using markers that represent the entire locus. METHODS: Five selected tagging polymorphisms were genotyped across a 65 kb region comprising the BDNF gene in a well established cohort of 250 unrelated German HD patients. RESULTS: Addition of BDNF genotype variations or one of the marker haplotypes to the effect of CAG repeat lengths did not affect the variance of the AO. CONCLUSION: We were unable to verify a recently reported association between the functional Val66Met polymorphism in the BDNF gene and AO in HD. From our findings, we conclude that neither sequence variations in nor near the gene contribute significantly to the variance of AO

Glutathione S-Transferase Ω 1 variation does not influence age at onset of Huntington's disease

BACKGROUND: Huntington's disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Circumstantial evidence suggests that additional features of the HD course are based on genetic traits. Therefore, it may be possible to investigate the genetic background of HD, i.e. to map the loci underlying the development and progression of the disease. Recently an association of Glutathione S-Transferase Ω 1 (GSTO1) and possibly of GSTO2 with AO was demonstrated for, both, Alzheimer's (AD) and Parkinson's disease (PD). METHODS: We have genotyped the polymorphisms rs4925 GSTO1 and rs2297235 GSTO2 in 232 patients with HD and 228 controls. RESULTS: After genotyping GSTO1 and GSTO2 polymorphisms, firstly there was no statistically significant difference in AO for HD patients, as well as secondly for HD patients vs. controls concerning, both, genotype and allele frequencies, respectively. CONCLUSION: The GSTO1 and GSTO2 genes flanked by the investigated polymorphisms are not comprised in a primary candidate region influencing AO in HD

Struktur-Wirkungs-Beziehungen für die ökotoxikologische Gefahrenpotenzialanalyse ausgewählter Isothiazol-3-on Biozide und Ionischer FlüssigkeitenEine wirkmechanismen-basierte Strategie

In the presented work two case studies using highly reactive Isothiazol-3-one biocides and Ionic liquids are presented. It was the aim of these studies to get a deeper knowledge on the hazard potential of the selected substances by applying a mode of action based testing strategy and a flexible toxicological and ecotoxicological test battery. Summarising the results obtained from both case studies, it could be shown that the applied tiered and mode of action based testing strategy in combination with a flexible test battery was a valuable tool to identify and screen modes of toxic action as well as structure-activity relationships of reactive and non-reactive chemicals. The identified hazard potentials of isothiazol-3-one biocides and ionic liquids reduced the uncertainty of their toxicological and ecotoxicological impacts and thus the obtained results can lead to a refined multidimensional risk assessment of these substances. Additionally, the uncovered structure-activity relationships can be used to design more inherently safer and hence sustainable biocides and ionic liquids. The used T-SAR based approach could be identified as a promising candidate for the above cited "intelligent testing strategies" in the hazard assessment of environmentally relevant chemicals

Structure-Activity Relationships for an Ecotoxicological Hazard Assessment of Selected Isothiazol-3-one Biocides and Ionic LiquidsA Mode-of-Action-Based Strategy

In the presented work two case studies using highly reactive Isothiazol-3-one biocides and Ionic liquids are presented. It was the aim of these studies to get a deeper knowledge on the hazard potential of the selected substances by applying a mode of action based testing strategy and a flexible toxicological and ecotoxicological test battery. Summarising the results obtained from both case studies, it could be shown that the applied tiered and mode of action based testing strategy in combination with a flexible test battery was a valuable tool to identify and screen modes of toxic action as well as structure-activity relationships of reactive and non-reactive chemicals. The identified hazard potentials of isothiazol-3-one biocides and ionic liquids reduced the uncertainty of their toxicological and ecotoxicological impacts and thus the obtained results can lead to a refined multidimensional risk assessment of these substances. Additionally, the uncovered structure-activity relationships can be used to design more inherently safer and hence sustainable biocides and ionic liquids. The used T-SAR based approach could be identified as a promising candidate for the above cited intelligent testing strategies in the hazard assessment of environmentally relevant chemicals

Molekulare Reorientierungen in polaren Fluessigkeiten und Polymeren

Arning H-J. Molekulare Reorientierungen in polaren Fluessigkeiten und Polymeren. Bielefeld; 1983