Abstract：
Nuclear exclusion of the RNA- and DNA-binding protein TDP-43 can induce neurodegeneration in different diseases. Diverse processes have been implicated to influence TDP-43 mislocalization, including disrupted nucleocytoplasmic transport (NCT); however, the physiological pathways that normally ensure TDP-43 nuclear localization are unclear. The six-transmembrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) cleaves the glycosylphosphatidylinositol (GPI) anchor that tethers some proteins to the membrane. Here we show that GDE2 maintains TDP-43 nuclear localization by regulating the dynamics of canonical Wnt signaling. Ablation of GDE2 causes aberrantly sustained Wnt activation in adult neurons, which is sufficient to cause NCT deficits, nuclear pore abnormalities, and TDP-43 nuclear exclusion. Disruption of GDE2 coincides with TDP-43 abnormalities in postmortem tissue from patients with amyotrophic lateral sclerosis (ALS). Further, GDE2 deficits are evident in human neural cell models of ALS, which display erroneous Wnt activation that, when inhibited, increases mRNA levels of genes regulated by TDP-43. Our study identifies GDE2 as a critical physiological regulator of Wnt signaling in adult neurons and highlights Wnt pathway activation as an unappreciated mechanism contributing to nucleocytoplasmic transport and TDP-43 abnormalities in disease.
摘要：
RNA和DNA结合蛋白TDP-43的核排斥可以在不同的疾病中诱导神经变性。影响TDP-43误定位的过程多种多样,包括破坏的核质运输（NCT）；然而，通常确保TDP-43核定位的生理途径尚不清楚.六跨膜酶甘油磷酸二酯磷酸二酯酶2（GDE2或GDPD5）裂解糖基磷脂酰肌醇（GPI）锚，将某些蛋白质连接到膜上。在这里，我们表明GDE2通过调节经典Wnt信号的动力学来维持TDP-43核定位。GDE2的消融导致成人神经元异常持续的Wnt激活，这足以导致NCT赤字，核孔隙异常，和TDP-43核排斥。GDE2的破坏与肌萎缩侧索硬化症（ALS）患者死后组织中的TDP-43异常相吻合。Further,GDE2缺陷在ALS的人类神经细胞模型中很明显，它显示错误的Wnt激活，当被抑制时，增加由TDP-43调节的基因的mRNA水平。我们的研究将GDE2确定为成人神经元中Wnt信号传导的关键生理调节因子，并强调Wnt通路激活是导致疾病中核质转运和TDP-43异常的未被理解的机制。
