The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity
Open accessAbstract
Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin–mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.
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Cites
Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
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The Role of Dynamin-Related Protein 1, a Mediator of Mitochondrial Fission, in Apoptosis
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S-Nitrosylation of Drp1 Mediates β-Amyloid-Related Mitochondrial Fission and Neuronal Injury
Cho, D.-H., Nakamura, T., Fang, J., Cieplak, P., Godzik, A., Gu, Z., & Lipton, S. A. (2009) · Science · doi:10.1126/science.1171091 · Cited by 1,092
Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
Panov, A. V., Gutekunst, C.-A., Leavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., & Greenamyre, J. T. (2002) · Nature Neuroscience · doi:10.1038/nn884 · Cited by 1,030
Self-citationThe dynamin-related GTPase Drp1 is required for embryonic and brain development in mice
Wakabayashi, J., Zhang, Z., Wakabayashi, N., Tamura, Y., Fukaya, M., Kensler, T. W., Iijima, M., & Sesaki, H. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200903065 · Cited by 667
Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro
Trushina, E., Dyer, R. B., Badger, J. D., Ure, D., Eide, L., Tran, D. D., Vrieze, B. T., Legendre-Guillemin, V., McPherson, P. S., Mandavilli, B. S., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.18.8195-8209.2004 · Cited by 520
Self-citationChoo, Y. S. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh162 · Cited by 515 · cited 2×
“Mutant HTT binds to mitochondria where it can accumulate in large oligomers12,23,24.”
Cited by
Mitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479
Mitochondrial Dynamics and Its Involvement in Disease
Chan, D. C. (2020) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012419-032711 · Cited by 1,416
Mitochondrial dynamics in health and disease: mechanisms and potential targets
Chen, W., Zhao, H., & Li, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01547-9 · Cited by 1,306
Mitochondrial Dysfunction in Neurodegenerative Diseases
Johri, A., & Beal, M. F. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.192138 · Cited by 806
Distinct fission signatures predict mitochondrial degradation or biogenesis.
Kleele, T., Rey, T., Winter, J., Zaganelli, S., Mahecic, D., Perreten Lambert, H., Ruberto, F. P., Nemir, M., Wai, T., Pedrazzini, T., et al. (2021) · Nature · doi:10.1038/s41586-021-03510-6 · Cited by 794
Metadata
- Authors
- Song, W., Chen, J., Petrilli, A., Liot, G., Klinglmayr, E., Zhou, Y., Poquiz, P., Tjong, J., Pouladi, M. A., Hayden, M. R., Masliah, E., Ellisman, M., Rouiller, I., Schwarzenbacher, R., Bossy, B., Perkins, G., & Bossy-Wetzel, E.
- Venue
- Nature Medicine
- Published
- 2011-02-20
- Volume
- 17
- Issue
- 3
- Pages
- 377-382
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2008584420
- Cited by
- 555
- References
- 8
- FWCI
- 17.39
- Type
- journal article
- Language
- en
- Open access
- green
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- Song, W., Chen, J., Petrilli, A., Liot, G., Klinglmayr, E., Zhou, Y., Poquiz, P., Tjong, J., Pouladi, M. A., Hayden, M. R., Masliah, E., Ellisman, M., Rouiller, I., Schwarzenbacher, R., Bossy, B., Perkins, G., & Bossy-Wetzel, E. (2011). Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nature Medicine. https://doi.org/10.1038/nm.2313
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