Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):E3138-47. doi: 10.1073/pnas.1301440110. Epub 2013 Jul 29.
Recent experimental evidence suggests that transcellular propagation of fibrillar protein aggregates drives the progression of neurodegenerative diseases in a prion-like manner. This phenomenon is now well described in cell and animal models and involves the release of protein aggregates into the extracellular space. Free aggregates then enter neighboring cells to seed further fibrillization. The mechanism by which aggregated extracellular proteins such as tau and α-synuclein bind and enter cells to trigger intracellular fibril formation is unknown. Prior work indicates that prion protein aggregates bind heparan sulfate proteoglycans (HSPGs) on the cell surface to transmit pathologic processes. Here, we find that tau fibril uptake also occurs via HSPG binding. This is blocked in cultured cells and primary neurons by heparin, chlorate, heparinase, and genetic knockdown of a key HSPG synthetic enzyme, Ext1. Interference with tau binding to HSPGs prevents recombinant tau fibrils from inducing intracellular aggregation and blocks transcellular aggregate propagation. In vivo, a heparin mimetic, F6, blocks neuronal uptake of stereotactically injected tau fibrils. Finally, uptake and seeding by α-synuclein fibrils, but not huntingtin fibrils, occurs by the same mechanism as tau. This work suggests a unifying mechanism of cell uptake and propagation for tauopathy and synucleinopathy.
最近的实验证据表明，纤维状蛋白聚集物的细胞间传播以类朊病毒的方式驱动神经退行性疾病的进展。这种现象在细胞和动物模型中得到了很好的描述，涉及到将蛋白聚集物释放到细胞外空间。游离的聚集物随后进入邻近的细胞，以引发进一步的纤维化。目前尚不清楚像 tau 和 α-突触核蛋白等细胞外聚集蛋白如何结合并进入细胞，从而引发细胞内纤维形成。先前的工作表明，朊病毒蛋白聚集物通过细胞表面的硫酸乙酰肝素蛋白聚糖 (HSPG) 结合来传递病理过程。在这里，我们发现 tau 纤维的摄取也通过 HSPG 结合发生。在培养的细胞和原代神经元中，肝素、氯酸盐、肝素酶以及关键 HSPG 合成酶 Ext1 的基因敲低会阻止这种情况的发生。干扰 tau 与 HSPG 的结合可防止重组 tau 纤维诱导细胞内聚集，并阻止细胞间聚集物的传播。在体内，肝素类似物 F6 可阻止立体定向注射的 tau 纤维被神经元摄取。最后，α-突触核蛋白纤维，而不是 huntingtin 纤维，通过与 tau 相同的机制发生摄取和播种。这项工作表明 tau 病和 synucleinopathy 的细胞摄取和传播具有统一的机制。
