Title |
Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets
|
---|---|
Published in |
Nature Medicine, December 2011
|
DOI | 10.1038/nm.2558 |
Pubmed ID | |
Authors |
Mali Jiang, Jiawei Wang, Jinrong Fu, Lin Du, Hyunkyung Jeong, Tim West, Lan Xiang, Qi Peng, Zhipeng Hou, Huan Cai, Tamara Seredenina, Nicolas Arbez, Shanshan Zhu, Katherine Sommers, Jennifer Qian, Jiangyang Zhang, Susumu Mori, X William Yang, Kellie L K Tamashiro, Susan Aja, Timothy H Moran, Ruth Luthi-Carter, Bronwen Martin, Stuart Maudsley, Mark P Mattson, Robert H Cichewicz, Christopher A Ross, David M Holtzman, Dimitri Krainc, Wenzhen Duan |
Abstract |
Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Uruguay | 1 | 33% |
Unknown | 2 | 67% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Science communicators (journalists, bloggers, editors) | 1 | 33% |
Practitioners (doctors, other healthcare professionals) | 1 | 33% |
Members of the public | 1 | 33% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 13 | 5% |
Germany | 2 | <1% |
Portugal | 2 | <1% |
Japan | 2 | <1% |
India | 1 | <1% |
Czechia | 1 | <1% |
Austria | 1 | <1% |
Mexico | 1 | <1% |
Belgium | 1 | <1% |
Other | 6 | 2% |
Unknown | 251 | 89% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 64 | 23% |
Researcher | 56 | 20% |
Student > Bachelor | 30 | 11% |
Student > Master | 20 | 7% |
Professor > Associate Professor | 18 | 6% |
Other | 59 | 21% |
Unknown | 34 | 12% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 106 | 38% |
Biochemistry, Genetics and Molecular Biology | 36 | 13% |
Neuroscience | 30 | 11% |
Medicine and Dentistry | 29 | 10% |
Chemistry | 11 | 4% |
Other | 22 | 8% |
Unknown | 47 | 17% |