SIRT1 通过激活分子伴侣来防止α-突触核蛋白聚集。
SIRT1 protects against α-synuclein aggregation by activating molecular chaperones.
机构信息
Paul F. Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
出版信息
J Neurosci. 2012 Jan 4;32(1):124-32. doi: 10.1523/JNEUROSCI.3442-11.2012.
Abstract
α-Synuclein is a key molecule in the pathogenesis of synucleinopathy including dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. Sirtuins are NAD(+)-dependent protein deacetylases that are highly conserved and counter aging in lower organisms. We show that the life span of a mouse model with A53T α-synuclein mutation is increased by overexpressing SIRT1 and decreased by knocking out SIRT1 in brain. Furthermore, α-synuclein aggregates are reduced in the brains of mice with SIRT1 overexpression and increased by SIRT1 deletion. We show that SIRT1 deacetylates HSF1 (heat shock factor 1) and increases HSP70 RNA and protein levels, but only in the brains of mice with A53T and SIRT1 expression. Thus, SIRT1 responds to α-synuclein aggregation-induced stress by activating molecular chaperones to protect against disease.
摘要
α-突触核蛋白是包括路易体痴呆、帕金森病和多系统萎缩在内的突触核蛋白病发病机制中的关键分子。沉默调节蛋白是 NAD(+)依赖的蛋白去乙酰化酶，在低等生物中高度保守，对抗衰老。我们发现，过表达 SIRT1 可延长 A53T α-突触核蛋白突变小鼠模型的寿命，而敲除大脑中的 SIRT1 则会缩短其寿命。此外，过表达 SIRT1 可减少小鼠大脑中的 α-突触核蛋白聚集，而 SIRT1 缺失则会增加其聚集。我们发现 SIRT1 可使 HSF1（热休克因子 1）去乙酰化，并增加 HSP70 RNA 和蛋白水平，但仅在 A53T 和 SIRT1 表达的小鼠大脑中如此。因此，SIRT1 通过激活分子伴侣对疾病产生保护作用，以响应 α-突触核蛋白聚集诱导的应激。
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本文引用的文献
1
Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway.
Nat Med. 2011 Dec 18;18(1):159-65. doi: 10.1038/nm.2559.
2
Acetylation of tau inhibits its degradation and contributes to tauopathy.
Neuron. 2010 Sep 23;67(6):953-66. doi: 10.1016/j.neuron.2010.08.044.
3
SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10.
Cell. 2010 Jul 23;142(2):320-32. doi: 10.1016/j.cell.2010.06.020.
4
Aging and disease: connections to sirtuins.
Aging Cell. 2010 Apr;9(2):285-90. doi: 10.1111/j.1474-9726.2010.00548.x.
5
The HSP70 molecular chaperone is not beneficial in a mouse model of alpha-synucleinopathy.
PLoS One. 2010 Apr 2;5(4):e10014. doi: 10.1371/journal.pone.0010014.
6
Mammalian sirtuins: biological insights and disease relevance.
Annu Rev Pathol. 2010;5:253-95. doi: 10.1146/annurev.pathol.4.110807.092250.
7
Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction.
Genes Dev. 2009 Dec 15;23(24):2812-7. doi: 10.1101/gad.1839209.
8
The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide.
J Neurochem. 2009 Sep;110(5):1445-56. doi: 10.1111/j.1471-4159.2009.06228.x. Epub 2009 Jun 22.
9
The role of molecular chaperones in human misfolding diseases.
FEBS Lett. 2009 Aug 20;583(16):2647-53. doi: 10.1016/j.febslet.2009.04.029. Epub 2009 Apr 23.
10
Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity.
Nat Genet. 2009 Mar;41(3):316-23. doi: 10.1038/ng.337. Epub 2009 Feb 22.
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