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

DOI: 10.1186/1750-1326-4-3

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Abstract:

Huntington's disease (HD [MIM 143100]; http://www.ncbi.nlm.nih.gov/Omim/ webcite) is one of the most common autosomal-dominant inherited neurodegenerative disorders. Clinically HD is characterized by motor and cognitive impairment, accompanied by a variable degree of personality change and psychiatric illness[1]. Advanced stages of HD are characterized by severe emaciation, despite a strong appetite and increased caloric intake[2,3]. HD is relentlessly progressive and patients succumb to the disease typically 10–25 years after disease onset[1]. In 1993, a CAG trinucleotide repeat expansion encoding an elongated polyglutamine tract in the huntingtin (HTT) protein was found to cause HD[4]. The number of CAG repeats in the htt gene is the most important, but not the only determinant of age at onset of HD. Depending on the populations studied, the number of CAG repeats in htt accounts for up to 73% of the variance in age at onset[5]. The remaining variation is strongly heritable[6]. Hence, modifier genes must contribute to the variability in age at onset of HD. The genetic modifiers identified so far include the huntingtin associated protein 1 (HAP1) gene and the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene [7-9]. The MAPS study, a genome-wide scan for modifier genes of age at onset using micro-satellite markers at a 10-cM density, suggested linkage at chromosomes 4p16, 6p21-23 and 6q24-26 and more marginal associations at several other sites, including 4p15 (marker D4S3403)[10].Recently, two independent groups presented evidence that the transcriptional co-regulator peroxisome proliferator-activated receptor γ (PPARγ) coactiavtor 1α (PGC-1α) plays a role in the neurodegeneration of HD [11-13]. PGC-1α regulates the expression of mitochondrial OXPHOS genes and endogenous antioxidants[14,15]. Mutant but not wild-type HTT down regulates the expression of this gene set[11,12]. Lack of PGC-1α expression produces a HD-like phenotype in mice and over-expression of PGC-

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