The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism
Abstract
The 'expanded' HD CAG repeat that causes Huntington's disease (HD) encodes a polyglutamine tract in huntingtin, which first targets the death of medium-sized spiny striatal neurons. Mitochondrial energetics, related to N-methyl-d-aspartate (NMDA) Ca2+-signaling, has long been implicated in this neuronal specificity, implying an integral role for huntingtin in mitochondrial energy metabolism. As a genetic test of this hypothesis, we have looked for a relationship between the length of the HD CAG repeat, expressed in endogenous huntingtin, and mitochondrial ATP production. In STHdhQ111 knock-in striatal cells, a juvenile onset HD CAG repeat was associated with low mitochondrial ATP and decreased mitochondrial ADP-uptake. This metabolic inhibition was associated with enhanced Ca2+-influx through NMDA receptors, which when blocked resulted in increased cellular [ATP/ADP]. We then evaluated [ATP/ADP] in 40 human lymphoblastoid cell lines, bearing non-HD CAG lengths (9-34 units) or HD-causing alleles (35-70 units). This analysis revealed an inverse association with the longer of the two allelic HD CAG repeats in both the non-HD and HD ranges. Thus, the polyglutamine tract in huntingtin appears to regulate mitochondrial ADP-phosphorylation in a Ca2+-dependent process that fulfills the genetic criteria for the HD trigger of pathogenesis, and it thereby determines a fundamental biological parameter--cellular energy status, which may contribute to the exquisite vulnerability of striatal neurons in HD. Moreover, the evidence that this polymorphism can determine energy status in the non-HD range suggests that it should be tested as a potential physiological modifier in both health and disease.
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Cites
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Self-citationEarly mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
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Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
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Mitochondrial defect in Huntington's disease caudate nucleus
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Alternative excitotoxic hypotheses
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Cited by
Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.5 · Cited by 1,641
Self-citationTrinucleotide Repeat Disorders
Orr, H. T., & Zoghbi, H. Y. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.29.051605.113042 · Cited by 1,368
Huntington disease: natural history, biomarkers and prospects for therapeutics
Ross, C. A., Aylward, E. H., Wild, E. J., Langbehn, D. R., Long, J. D., Warner, J. H., Scahill, R. I., Leavitt, B. R., Stout, J. C., Paulsen, J. S., et al. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.24 · Cited by 1,016
Ageing and neuronal vulnerability
Mattson, M. P., & Magnus, T. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1886 · Cited by 957
Weydt, P., Pineda, V. V., Torrence, A. E., Libby, R. T., Satterfield, T. F., Lazarowski, E. R., Gilbert, M. L., Morton, G. J., Bammler, T. K., Strand, A. D., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.10.004 · Cited by 562
Metadata
- Authors
- Seong, I. S., Ivanova, E., Lee, J.-M., Choo, Y. S., Fossale, E., Anderson, M., Gusella, J. F., Laramie, J. M., Myers, R. H., Lesort, M., & MacDonald, M. E.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-08-22
- Volume
- 14
- Issue
- 19
- Pages
- 2871-2880
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2157590258
- Cited by
- 294
- References
- 62
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- closed
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- Seong, I. S., Ivanova, E., Lee, J.-M., Choo, Y. S., Fossale, E., Anderson, M., Gusella, J. F., Laramie, J. M., Myers, R. H., Lesort, M., & MacDonald, M. E. (2005). HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddi319
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