The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.
The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.
复制标题
在帕金森病模型中sirtuin 2介导的α-突触核蛋白毒性加重的机制。
DOI：
10.1371/journal.pbio.2000374
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发表时间：
2017-03
期刊：
影响因子：
9.8
通讯作者：
Outeiro TF
中科院分区：
文献类型：
--
作者：
de Oliveira RM;Vicente Miranda H;Francelle L;Pinho R;Szegö ÉM;Martinho R;Munari F;Lázaro DF;Moniot S;Guerreiro P;Fonseca-Ornelas L;Marijanovic Z;Antas P;Gerhardt E;Enguita FJ;Fauvet B;Penque D;Pais TF;Tong Q;Becker S;Kügler S;Lashuel HA;Steegborn C;Zweckstetter M;Outeiro TF
Sirtuin基因与衰老有关，并已知影响多种细胞途径。Sirtuin 2以前被证明可以调节与年龄相关的神经退行性疾病相关的蛋白毒性，如阿尔茨海默病和帕金森病(PD)。然而，涉及的确切分子机制仍不清楚。在这里，我们提供了对sirtuin2和α-突触核蛋白之间相互作用的机械性见解，突触核蛋白是帕金森病和其他突触核病病原蛋白包涵体的主要成分。我们发现α-突触核蛋白在赖氨酸6和10上是乙酰化的，并且这些残基被sirtuin 2去乙酰化。体内外对sirtuin 2水平的遗传操作调节了α-突触核蛋白乙酰化水平、其聚集和自噬。引人注目的是，阻断乙酰化的突变体加剧了体内大鼠黑质中α-突触核蛋白的毒性。我们的研究发现α-突触核蛋白乙酰化是α-突触核蛋白聚集和毒性的关键调节机制，证明了抑制sirtuin 2在突触核病中的潜在治疗价值。帕金森病是一种与年龄相关的神经退行性疾病，其特征是大脑黑质区域产生多巴胺的神经元丢失，并在细胞内包涵体中积聚蛋白质α-突触核蛋白。这些包涵体是病理过程的原因还是结果仍不清楚。Sirtuin蛋白被认为是衰老过程的主要调节蛋白，以前曾被认为与神经退化有关。在这项研究中，我们研究了sirtuin 2和α-突触核蛋白之间的相互作用，以剖析与保护α-突触核蛋白毒性相关的分子机制。我们发现sirtuin 2与α-突触核蛋白中的乙酰基相互作用并将其去掉。通过降低sirtuin 2的水平，或通过表达α-突触核蛋白的突变版本来调节其乙酰化状态，我们发现乙酰化在体外减少了α-突触核蛋白的聚集及其细胞毒性。接下来，我们评估了sirtuin 2的基因抑制是否可以在体内阻止α-突触核蛋白的有害影响，并发现在两种不同的帕金森病模型中，sirtuin 2的缺失具有神经保护作用。因此，我们的数据表明，旨在降低sirtuin 2活性的策略可能被证明是干预帕金森病和其他突触核病的有价值的治疗途径。
Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies. Parkinson disease is an age-associated neurodegenerative disorder characterized by the loss of dopamine-producing neurons from a region in the brain known as the substantia nigra and by the accumulation of the protein alpha-synuclein in intracellular clumps called inclusions. Whether these inclusions are the cause or a consequence of the pathological processes is still unclear. Sirtuin proteins are considered master regulators of the ageing process and have previously been associated with neurodegeneration. In this study, we investigated the interplay between sirtuin 2 and alpha-synuclein in order to dissect the molecular mechanisms associated with protection against alpha-synuclein toxicity. We found that sirtuin 2 interacted with and removed acetyl groups from alpha-synuclein. By decreasing the levels of sirtuin 2, or by expressing mutant versions of alpha-synuclein that modulate its acetylation status, we found that acetylation reduces the aggregation of alpha-synuclein and its cytotoxicity in vitro. Next, we evaluated whether genetic inhibition of sirtuin 2 could prevent the deleterious effects of alpha-synuclein in vivo and found that, in two different models of Parkinson disease, deletion of sirtuin 2 was neuroprotective. Our data therefore suggest that strategies aimed at decreasing sirtuin 2 activity might prove valuable therapeutic avenues for intervention in Parkinson disease and other synucleinopathies.