Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
PLoS One. 2012;7(10):e47073. doi: 10.1371/journal.pone.0047073. Epub 2012 Oct 4.
Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by Aβ aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway.
树突分支对于神经元的正常连接至关重要。SIRT1 是一种 NAD+依赖的组蛋白去乙酰化酶，与衰老和长寿有关，在神经元中与神经元分化和神经保护有关。在本研究中，通过转染在体外培养的海马神经元，评估了 SIRT1 在树突发育中的作用。转染的神经元表达 SIRT1 或缺乏催化活性的 SIRT1H363Y 显性负性突变体。过表达 SIRT1 的神经元表现出树突分支增加，而过表达 SIRT1H363Y 的神经元表现出树突复杂性降低。SIRT1 的作用可以通过处理白藜芦醇来模拟，白藜芦醇是一种众所周知的 SIRT1 激活剂，对过表达 SIRT1H363Y 的神经元没有作用，这表明白藜芦醇的作用是由 SIRT1 特异性介导的。此外，过表达 SIRT1 的海马神经元对 Aβ 聚集物诱导的树突萎缩具有抗性，这种作用依赖于 SIRT1 的去乙酰化酶活性。我们的发现表明，SIRT1 在海马神经元的树突分支发育和维持中发挥作用，并表明这些作用是通过 ROCK 信号通路介导的。
