Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California 92093, USA.
J Biol Chem. 2012 Sep 14;287(38):31691-702. doi: 10.1074/jbc.M112.354522. Epub 2012 Jul 25.
Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of α-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that α-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that α-synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for α-synuclein-mediated disruption of adult neurogenesis in Parkinson disease.
帕金森病的特征是多巴胺能神经元主要在黑质中丧失。在许多其他脑区，包括海马体，也有α-突触核蛋白的积累和细胞丢失，这可能损害成年神经发生，导致非运动症状。然而，这些改变的分子机制仍不清楚。在本报告中，我们显示了α-突触核蛋白聚集的成年大鼠海马体神经祖细胞表现出异常的神经元分化，Notch1 表达和下游信号靶标减少。我们描述了一个包含 p53 经典反应元件的 Notch1 近端启动子。p53 在体内结合抑制神经元中 Notch1 的转录。此外，我们证明α-突触核蛋白直接与 Notch1 启动子附近的 DNA 结合，也与 p53 蛋白相互作用，促进或增加 Notch1 信号抑制，从而干扰神经祖细胞的成熟和存活。这项研究为帕金森病中α-突触核蛋白介导的成年神经发生破坏提供了分子基础。
