PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease
<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 a...
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| Format: | Article |
| Language: | English |
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BMC
2011-05-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | http://www.molecularneurodegeneration.com/content/6/1/32 |
| _version_ | 1811328967686225920 |
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| author | Haghikia Aiden Wieczorek Stefan Akkad Denis A Saft Carsten Taherzadeh-Fard Elahe Chan Andrew Epplen Jörg T Arning Larissa |
| author_facet | Haghikia Aiden Wieczorek Stefan Akkad Denis A Saft Carsten Taherzadeh-Fard Elahe Chan Andrew Epplen Jörg T Arning Larissa |
| author_sort | Haghikia Aiden |
| collection | DOAJ |
| description | <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> |
| first_indexed | 2024-04-13T15:34:13Z |
| format | Article |
| id | doaj.art-4425634951c24054bec1d06e2015d5b5 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-04-13T15:34:13Z |
| publishDate | 2011-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-4425634951c24054bec1d06e2015d5b52022-12-22T02:41:18ZengBMCMolecular Neurodegeneration1750-13262011-05-01613210.1186/1750-1326-6-32PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington diseaseHaghikia AidenWieczorek StefanAkkad Denis ASaft CarstenTaherzadeh-Fard ElaheChan AndrewEpplen Jörg TArning Larissa<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>http://www.molecularneurodegeneration.com/content/6/1/32 |
| spellingShingle | Haghikia Aiden Wieczorek Stefan Akkad Denis A Saft Carsten Taherzadeh-Fard Elahe Chan Andrew Epplen Jörg T Arning Larissa PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease Molecular Neurodegeneration |
| title | PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease |
| title_full | PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease |
| title_fullStr | PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease |
| title_full_unstemmed | PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease |
| title_short | PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease |
| title_sort | pgc 1alpha downstream transcription factors nrf 1 and tfam are genetic modifiers of huntington disease |
| url | http://www.molecularneurodegeneration.com/content/6/1/32 |
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