| Summary: | <p>Abstract</p> <p>Background</p> <p>Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin <it>HTT </it>(<it>HD</it>) gene. The primary genetic determinant of the age at onset (AO) is the length of the <it>HTT </it>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 <it>gamma </it>coactivator 1a (PGC-1<it>alpha</it>) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1<it>alpha </it>in HD pathogenesis was generated by the findings that sequence variations in the <it>PPARGC1A </it>gene encoding PGC-1<it>alpha </it>exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1<it>alpha </it>downstream targets might also contribute to the variation in the AO.</p> <p>Results</p> <p>In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, <it>NRF-1</it>, and the mitochondrial transcription factor A, encoded by <it>TFAM </it>showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in <it>PPARGC1A </it>and C7028T in the <it>cytochrome c oxidase subunit I </it>(<it>CO1</it>, 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.</p> <p>Conclusions</p> <p>These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1<it>alpha </it>may be useful targets in the treatment of HD.</p>
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