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Cited by 134Genetic Neurodegenerative DiseasesHereditary Neurological DisordersMitochondrial Function and Pathology

PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease

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Taherzadeh-Fard, Elahe, Saft, Carsten, Akkad, Denis A, Wieczorek, Stefan, Haghikia, Aiden, Chan, Andrew, Epplen, Jörg T, Arning, Larissa·2011·Molecular Neurodegeneration
DOI 10.1186/1750-1326-6-32PMC PMC3117738
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Abstract

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

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Authors
Taherzadeh-Fard, E., Saft, C., Akkad, D. A., Wieczorek, S., Haghikia, A., Chan, A., Epplen, J. T., & Arning, L.
Affiliations
  • Ruhr University Bochum (DE)
  • St. Josef-Hospital (DE)
Corresponding author
Arning, Larissa
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2011-05-19
Volume
6
Issue
1
Pages
32-32
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/1750-1326-6-32
PMC
PMC3117738
OpenAlex
W2133198467
Cited by
134
References
3
Citations by year
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FWCI
2.63
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Huntington's disease, PGC-1α, NRF1, TFAM, age of onset, genetic modifiers, mitochondrial dysfunction, CAG repeat expansion, gene-gene interaction, mitochondrial transcription factors

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