Department of Biological Sciences, University of the Sciences, Philadelphia, United States.
Program in Neuroscience, University of the Sciences, Philadelphia, United States.
Elife. 2020 May 28;9:e58499. doi: 10.7554/eLife.58499.
Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell to cell through the brain in a manner akin to infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal activity and blocked by inhibiting caspases in presynaptic neurons, implicating synaptic dysfunction and cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires the glial scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected neurons. These findings expand our understanding of phagocytic glia as double-edged players in neurodegeneration-by clearing neurotoxic protein aggregates, but also providing an opportunity for prion-like seeds to evade phagolysosomal degradation and propagate further in the brain.
新兴证据支持这样一种假说，即与神经退行性疾病相关的致病蛋白聚集体通过类似于传染性朊病毒的方式在大脑中从一个细胞传播到另一个细胞。在这里，我们表明，与亨廷顿病相关的突变亨廷顿蛋白（mHtt）聚集体在成年嗅觉系统中从前一个神经元向前一个神经元顺行传递。mHtt 聚集体的跨突触传递与神经元活动呈负相关，并可通过抑制前一个神经元中的半胱天冬酶来阻断，这表明突触功能障碍和细胞死亡与聚集体的扩散有关。值得注意的是，mHtt 聚集体跨越突触的传递需要胶质吞噬受体 Draper，并且涉及到对神经胶质细胞质的短暂访问，这表明吞噬性神经胶质细胞作为连接突触的神经元之间聚集体扩散的必需中间物。这些发现扩展了我们对吞噬性神经胶质细胞作为神经退行性变双刃剑的理解——通过清除神经毒性蛋白聚集体，但也为朊病毒样种子提供了逃避吞噬体降解和在大脑中进一步传播的机会。
