Abstract:
The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD. AVLX-144-based probes were labeled with the radioisotopes fluorine-18 and tritium, as well as a fluorescent tag. Tracer binding showed saturable, displaceable, and uneven distribution in rat brain slices, proving effective in quantitative autoradiography and cell imaging studies. Notably, we observed diminished tracer binding in human post-mortem Parkinson\'s disease (PD) brain slices, suggesting postsynaptic impairment in PD. We thus offer a suite of translational probes for visualizing and understanding PSD-related pathologies.
摘要:
突触后密度(PSD)包含许多支架蛋白,受体,和协调大脑中突触传递的信号分子。突触后密度蛋白95(PSD-95)是PSD内的主要支架蛋白,是其最丰富的蛋白之一,因此构成了PSD功能及其病理变化的非常有吸引力的生物标志物。这里,我们利用PSD-95的高亲和力抑制剂AVLX-144作为开发PSD分子成像探针的模板。基于AVLX-144的探针用放射性同位素氟-18和tri标记,以及荧光标签。示踪剂结合显示饱和,可移动,在大鼠脑片中分布不均,证明在定量放射自显影和细胞成像研究中有效。值得注意的是,我们观察到人类死后帕金森病(PD)脑切片中示踪剂结合减少,提示PD的突触后损伤。因此,我们提供了一套用于可视化和理解PSD相关病理的翻译探针。