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PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease.

Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L - Mol Neurodegener (2011)

Bottom Line: In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD.When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, Ruhr-University Bochum, Germany. larissa.arning@rub.de.

ABSTRACT

Background: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.

Results: In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

Conclusions: These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

No MeSH data available.


Related in: MedlinePlus

ATP concentration in HD patients. Box plot shows medians, quartiles and extreme values. The mean ATP levels of HD patients with the TT genotype (600.6 ± 48.7 ng, n = 9) and those carrying at least one rare NRF-1 rs7781972 allele (TA and AA, 487.1 ± 179 ng, n = 8; 436.7 ± 135.1 ng, n = 4) were significantly different (p = 0.03 two-sample t test).
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Figure 2: ATP concentration in HD patients. Box plot shows medians, quartiles and extreme values. The mean ATP levels of HD patients with the TT genotype (600.6 ± 48.7 ng, n = 9) and those carrying at least one rare NRF-1 rs7781972 allele (TA and AA, 487.1 ± 179 ng, n = 8; 436.7 ± 135.1 ng, n = 4) were significantly different (p = 0.03 two-sample t test).

Mentions: When correlating the ATP concentrations with the NRF-1 and TFAM genotypes, HD patients carrying at least one rare NRF-1 rs7781972 allele showed significantly lower ATP concentrations (487.1 ± 179 ng, n = 8; 436.7 ± 135.1 ng, n = 4) than homozygous individuals carrying the frequent allele (600.6 ± 48.7 ng, n = 9, p = 0.03; Figure 2). Considering an additive allele effect the ATP levels were negatively correlated with the rare NRF-1 rs7781972 allele (Pearson coefficient -0.478, p < 0.029). Yet, this effect was not obvious in a group of 38 healthy controls (529 ± 175.5 ng, n = 14; 487.4 ± 148 ng, n = 22 vs. 492 ± 120.5 ng, n = 2, Pearson coefficient -0.130, p < 0.437). In both groups the ATP levels were not significantly correlated with the mtDNA:nDNA ratios (HD: Spearman coefficient -0.383, p < 0.095, controls: 0.134, p < 0.417). Regarding the entire patient cohort (n = 401), the mtDNA content was also not associated with age, sex, AO, disease duration, CAG repeat lengths or any other genotype.


PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease.

Taherzadeh-Fard E, Saft C, Akkad DA, Wieczorek S, Haghikia A, Chan A, Epplen JT, Arning L - Mol Neurodegener (2011)

ATP concentration in HD patients. Box plot shows medians, quartiles and extreme values. The mean ATP levels of HD patients with the TT genotype (600.6 ± 48.7 ng, n = 9) and those carrying at least one rare NRF-1 rs7781972 allele (TA and AA, 487.1 ± 179 ng, n = 8; 436.7 ± 135.1 ng, n = 4) were significantly different (p = 0.03 two-sample t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117738&req=5

Figure 2: ATP concentration in HD patients. Box plot shows medians, quartiles and extreme values. The mean ATP levels of HD patients with the TT genotype (600.6 ± 48.7 ng, n = 9) and those carrying at least one rare NRF-1 rs7781972 allele (TA and AA, 487.1 ± 179 ng, n = 8; 436.7 ± 135.1 ng, n = 4) were significantly different (p = 0.03 two-sample t test).
Mentions: When correlating the ATP concentrations with the NRF-1 and TFAM genotypes, HD patients carrying at least one rare NRF-1 rs7781972 allele showed significantly lower ATP concentrations (487.1 ± 179 ng, n = 8; 436.7 ± 135.1 ng, n = 4) than homozygous individuals carrying the frequent allele (600.6 ± 48.7 ng, n = 9, p = 0.03; Figure 2). Considering an additive allele effect the ATP levels were negatively correlated with the rare NRF-1 rs7781972 allele (Pearson coefficient -0.478, p < 0.029). Yet, this effect was not obvious in a group of 38 healthy controls (529 ± 175.5 ng, n = 14; 487.4 ± 148 ng, n = 22 vs. 492 ± 120.5 ng, n = 2, Pearson coefficient -0.130, p < 0.437). In both groups the ATP levels were not significantly correlated with the mtDNA:nDNA ratios (HD: Spearman coefficient -0.383, p < 0.095, controls: 0.134, p < 0.417). Regarding the entire patient cohort (n = 401), the mtDNA content was also not associated with age, sex, AO, disease duration, CAG repeat lengths or any other genotype.

Bottom Line: In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD.When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, Ruhr-University Bochum, Germany. larissa.arning@rub.de.

ABSTRACT

Background: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO.

Results: In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively.

Conclusions: These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

No MeSH data available.


Related in: MedlinePlus