Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease

Abstract

BackgroundHuntington disease (HD) is caused by a polyglutamine expansion of more than 35 units in the huntingtin protein. This expanded repeat length inversely correlates with the age-at-onset (AAO), however, additional genetic factors apart from the expanded CAG repeat size are thought to influence the course and the AAO in HD. Until now, among others, the gene encoding PCG-1α (PPARGC1A) was shown to modify the AAO in two independent, however small, populations. PGC-1α is involved in the induction of various mechanisms regulating mitochondrial biogenesis and oxidative stress defence. Furthermore, several studies have linked impairment of its function and/or its expression to HD pathogenesis. As the identification of distinct modifiers in association studies is largely dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNPs) in PPARGC1A in order to replicate the disease modifying effect in more than 800 European HD patients and to identify an association with AAO in HD.ResultsTwo SNPs, one in the promoter and one in the transcribed region of the gene, showed a significant effect on the AAO. While the minor allele of SNP rs7665116 (g.38570C), located in the transcribed gene region, was associated with a delay in disease onset, especially in HD patients with Italian ancestry, the minor allele of SNP rs2970870 (g.-1437C) in the promoter region leads to an earlier onset of HD in its homozygous state. Additionally, global testing of haplotype block 2, which covers the main part of the transcribed region of the gene, revealed an association between block 2 haplotypes and the disease onset.ConclusionTherefore, our results indicate opposing modifying influences of two SNPs within one gene on AAO and support the idea that PGC-1α dysfunction is involved in HD pathology.

mRNA Expression Levels of PGC-1α in a Transgenic and a Toxin Model of Huntington’s Disease

“…Supporting the role of PGC-1a gene in HD, it has also been implicated as a candidate modifier gene in HD; indeed, a number of variations demonstrated modifying effects on the age at onset (AO) (Taherzadeh-Fard et al 2009;Weydt et al 2009;Che et al 2011;Soyal et al 2012). Among them, the rs7665116 polymorphism has been proven to have significant association with AO, i.e., its presence was related to a protective effect in three European HD cohorts (Taherzadeh-Fard et al 2009;Weydt et al 2009;Che et al 2011).…”

“…Among them, the rs7665116 polymorphism has been proven to have significant association with AO, i.e., its presence was related to a protective effect in three European HD cohorts (Taherzadeh-Fard et al 2009;Weydt et al 2009;Che et al 2011). However, Ramus et al could not confirm these results (Ramos et al 2012), which contradiction may be explained by the difference in the genetic backgrounds of the different populations examined.…”

Autophagy in Alzheimer’s disease

“…These ubiquitous trans-membrane proteins have diverse biological roles in wnt signaling pathway, calcium channel regulation, cell adhesion, apoptosis, neurite outgrowth and synaptic plasticity [51, 52] (reviewed in [53]). There is now evidence that PSs may also play a role in mediating autophagy.…”

Potential roles of PINK1 for increased PGC-1α-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes

“…A recent study indicated an important role of PGC-1α in AD (Sheng et al, 2012), Parkinson disease (PD) (Shin et al, 2011), Huntington disease (HD) (Cui et al, 2006; Johri et al, 2011), and amyotrophic lateral sclerosis (ALS) (Liang et al, 2011; Zhao et al, 2011) as well as diabetes (Benton et al, 2010). Single-nucleotide polymorphisms in PPARGC1A , the gene encoding PGC-1α, are associated with the age onset in HD and PD (Clark et al, 2011; Che et al, 2011), and with conversion from impaired glucose tolerance to diabetes (Esterbauer et al, 1999). The PGC-1α null mouse displays severe systemic mitochondrial and metabolic abnormalities, and spongiform neurodegeneration (Lin et al, 2004).…”