Department of Anesthesiology, Stony Brook School of Medicine, NY 11794, USA.
Department of Anesthesiology, Stony Brook School of Medicine, NY 11794, USA; Department of Neurobiology and Behavior, Stony Brook University, NY 11794, USA.
Curr Biol. 2019 Oct 7;29(19):3135-3152.e4. doi: 10.1016/j.cub.2019.07.071. Epub 2019 Sep 5.
A hallmark of neurodegenerative disease is focal onset of pathological protein aggregation, followed by progressive spread of pathology to connected brain regions. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), pathology is often associated with aggregation of TAR DNA-binding protein 43 (TDP-43). Although aggregated TDP-43 protein moves between cells, it is not clear whether and how this movement propagates the degeneration. Here, we have established a Drosophila model of human TDP-43 in which we initiated toxic expression of human TDP-43 focally within small groups of glial cells. We found that this focal onset kills adjacent neurons. Surprisingly, we show that this spreading death is caused by an endogenous retrovirus within the glia, which leads to DNA damage and death in adjacent neurons. These findings suggest a possible mechanism by which human retroviruses such as HERV-K might contribute to TDP-43-mediated propagation of neurodegeneration.
神经退行性疾病的一个标志是病理性蛋白质聚集的局灶性发作，随后病理逐渐扩散到相连的脑区。在肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）中，病理通常与 TAR DNA 结合蛋白 43（TDP-43）的聚集有关。尽管聚集的 TDP-43 蛋白在细胞之间移动，但尚不清楚这种运动是否以及如何传播变性。在这里，我们建立了一个果蝇模型，其中我们在一小群神经胶质细胞内局部诱导人 TDP-43 的毒性表达。我们发现这种局灶性发作会杀死相邻的神经元。令人惊讶的是，我们表明这种扩散性死亡是由神经胶质细胞内的内源性逆转录病毒引起的，它会导致相邻神经元的 DNA 损伤和死亡。这些发现表明，人类逆转录病毒（如 HERV-K）可能通过何种机制导致 TDP-43 介导的神经退行性变的传播。
