Short report

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

Patrick Weydt^1* , Selma M Soyal^2* , Cinzia Gellera³ , Stefano DiDonato³ , Claus Weidinger² , Hannes Oberkofler² , G Bernhard Landwehrmeyer¹ and Wolfgang Patsch¹

¹  Department of Neurology, University of Ulm (P.W.; G.B.L.), Ulm, Germany

²  Department of Laboratory Medicine, Paracelsus Medical University and Universitätsklinikum Salzburg (S.M.S.; C.W.; H.O.; W.P.), Salzburg, Austria

³  Division of Biochemistry and Genetics, Fondazione IRCCS – Instituto Neurologico, C. Besta (C.G.; S.D.), Milan, Italy

author email corresponding author email* Contributed equally

Molecular Neurodegeneration 2009, 4:3doi:10.1186/1750-1326-4-3

Published:	8 January 2009

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-1α, 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-1α. 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-1α system on the course of Huntington's disease in humans.