Novel FTY720-Based Compounds Stimulate Neurotrophin Expression and Phosphatase Activity in Dopaminergic Cells
Novel FTY720-Based Compounds Stimulate Neurotrophin Expression and Phosphatase Activity in Dopaminergic Cells
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DOI：
10.1021/ml500128g
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发表时间：
2014-07-01
影响因子：
4.2
通讯作者：
Perez, Ruth G.
中科院分区：
文献类型：
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作者：
Vargas-Medrano, Javier;Krishnamachari, Sesha;Perez, Ruth G.
α-突触核蛋白是一种与帕金森病（PD）有关的分子伴侣样蛋白。在α-synudein的正常功能中，有能力在体外和体内结合并刺激蛋白磷酸酶2A（PP 2A）催化亚基的活性。PP 2A活性在PD和路易体痴呆中受损，路易体位于含有α-synudein聚集体的脑区域。使用PP 2A作为读数，我们测量了PP 2A对α-synudein，神经酰胺和FTY 720的反应活性，然后在这些结果的基础上，我们创造了新的FTY 720化合物。然后，我们测量了这些化合物在多巴酚丁胺能细胞中的作用。除了刺激PP 2A，所有三种化合物刺激脑源性神经营养因子的表达，并保护MN 9D细胞免受肿瘤坏死因子-α相关的细胞死亡。FTY 720-C2似乎更有效，而FTY 720-Mitoxy靶向线粒体。重要的是，FTY 720已经被FDA批准用于治疗多发性硬化症，并在全球范围内临床使用。我们的研究结果表明，FTY 720和我们的新FTY 720为基础的化合物具有相当大的潜力，用于治疗突触核蛋白病，如PD。
alpha-Synuclein is a chaperone-like protein implicated in Parkinson's disease (PD). Among alpha-synudein's normal functions is an ability to bind to and stimulate the activity of the protein phosphatase 2A (PP2A) catalytic subunit in vitro and in vivo. PP2A activity is impaired in PD and in dementia with Lewy Bodies in brain regions harboring alpha-synudein aggregates. Using PP2A as the readout, we measured PP2A activity in response to a-synudein, ceramides, and FTY720, and then on the basis of those results, we created new FTY720 compounds. We then measured the effects of those compounds in doparminergic cells. In addition to stimulating PP2A, all three compounds stimulated the expression of brain derived neurotrophic factor and protected MN9D cells against tumor-necrosis-factor-alpha-associated cell death. FTY720-C2 appears to be more potent while FTY720-Mitoxy targets mitochondria. Importantly, FTY720 is already FDA approved for treating multiple sclerosis and is used clinically worldwide. Our findings suggest that FTY720 and our new FTY720-based compounds have considerable potential for treating synucleinopathies such as PD.