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The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease.

ABSTRACT: Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predictor of disease-onset, but the remaining variation is strongly heritable. Transcriptional dysregulation, mitochondrial dysfunction and enhanced oxidative stress have been implicated in the pathogenesis. Recent studies suggest that PGC-1alpha, a transcriptional master regulator of mitochondrial biogenesis and metabolism, is defective in HD. A genome wide search for modifier genes of HD age-of-onset had suggested linkage at chromosomal region 4p16-4p15, near the locus of PPARGC1A, the gene coding for PGC-1alpha. We now present data of 2-loci PPARGC1A block 2 haplotypes, showing an effect upon age-at-onset in 447 unrelated HD patients after statistical consideration of CAG repeat lengths in both HTT alleles. Block 1 haplotypes were not associated with the age-at-onset. Homozygosity for the 'protective' block 2 haplotype was associated with a significant delay in disease onset. To our knowledge this is the first study to show clinically relevant effects of the PGC-1alpha system on the course of Huntington's disease in humans.

SUBMITTER: Weydt P

PROVIDER: S-EPMC2630305 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease.

Weydt Patrick P Soyal Selma M SM Gellera Cinzia C Didonato Stefano S Weidinger Claus C Oberkofler Hannes H Landwehrmeyer G Bernhard GB Patsch Wolfgang W

Molecular neurodegeneration 20090108

Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predi ...[more]

PMID: 19133136

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Project description:BackgroundPeroxisome proliferator-activated receptor-γ co-activator (PGC)-1α is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1α. We hypothesized that the rs8192678 PGC-1α single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1α SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP.MethodsGenomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model.ResultsThe rs8192678 PGC-1α SNP was not associated with the risk of PD. However, an association of the PGC-1α rs8192678 GG variant with longevity was seen in control subjects (p=0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p=0.029), with PD age of onset (p=0.047), and with longevity (p=0.022). The rs2970848 GG allele was associated with risk of late onset PD (p=0.027).ConclusionsThese data reveal possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1α in PD and longevity.

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The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease.

Publications

The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease.

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