Neuroprotective role of SIRT1 in mammalian models of Huntington’s disease through activation of multiple SIRT1 targets

By Mali Jiang, Jiawei Wang, Jinrong Fu, L. Du, Hyunkyung Jeong, T. West, Lan Xiang, Qi Peng, Zhipeng Hou, Huan Cai and 20 more. Nature Medicine, 2011

343 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/7f9d4dd4cb2962904055a90abf48ef40df7d610b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. M. Beal
2. A. Johri
3. D. Sinclair
4. Mark P. Mattson
5. S. Camandola
6. P. Reddy
7. Michael T. Heneka
8. M. O’Banion

In Geriatrics and Gerontology

1. D. Sinclair
2. Alexander S. Banks

In Physiology

1. M. Beal
2. D. Sinclair
3. Mark P. Mattson
4. A. Johri
5. T. Horvath
6. S. Camandola
7. Alexander S. Banks
8. M. O’Banion

Citations in the corpus

• SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “Recent studies have suggested that SIRT1 is responsible for protection from neuronal, and specifically axonal, degeneration (16, 90, 169, 336), suggesting that the activation of SIRT1 might be important in the treatment of Alzheimer’s disease or other neurodegenerative diseases such as Huntington’s ”
• Brain metabolism in health, aging, and neurodegeneration (2017, positive): “Evidence suggests that the lysine deacetylases sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3) can preserve mitochondrial function and protect striatal neurons against dysfunction and degeneration (Jeong et al, 2011; Jiang et al, 2011; Fu et al, 2012).”
• Mitochondrial Dysfunction in Neurodegenerative Diseases (2012, background): “PGC-1 activity is modulated by SIRT1, an NAD-dependent deacetylase, and activation of SIRT1 is protective in models of HD (Jeong et al., 2012; Jiang et al., 2012).”