法布里病神经元功能障碍模型系统的开发。
Development of a model system for neuronal dysfunction in Fabry disease.
作者信息
Kaneski Christine R, Brady Roscoe O, Hanover John A, Schueler Ulrike H
机构信息
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Mol Genet Metab. 2016 Sep;119(1-2):144-50. doi: 10.1016/j.ymgme.2016.07.010. Epub 2016 Jul 22.
Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). It is a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. One of the hallmarks of this disorder is neuropathic pain and sympathetic and parasympathetic nervous dysfunction. The exact mechanism by which changes in AGA activity result in change in neuronal function is not clear, partly due to of a lack of relevant model systems. In this study, we report the development of an in vitro model system to study neuronal dysfunction in Fabry disease by using short-hairpin RNA to create a stable knock-down of AGA in the human cholinergic neuronal cell line, LA-N-2. We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene-silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to study specific neuronal functions such as neurotransmitter release in Fabry disease.
法布里病是一种糖鞘脂贮积症，由α - 半乳糖苷酶A（AGA，EC 3.2.1.22）的基因缺陷引起。它是一种多系统疾病，会影响血管、心脏、肾脏和神经系统。这种疾病的一个特征是神经性疼痛以及交感和副交感神经功能障碍。AGA活性变化导致神经元功能改变的确切机制尚不清楚，部分原因是缺乏相关的模型系统。在本研究中，我们报告了一种体外模型系统的开发，该系统通过使用短发夹RNA在人胆碱能神经元细胞系LA - N - 2中稳定敲低AGA，来研究法布里病中的神经元功能障碍。我们表明，基因沉默的细胞显示出AGA活性特异性降低，并储存球三糖神经酰胺。在基因沉默的细胞中，神经递质乙酰胆碱的释放显著减少，这表明该模型可用于研究法布里病中特定的神经元功能，如神经递质释放。
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