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.

中文翻译：

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神经元 Wnt 活性的生理调节对于 TDP-43 定位和功能至关重要。


RNA 和 DNA 结合蛋白 TDP-43 的核排斥可诱导不同疾病中的神经变性。多种过程可能影响 TDP-43 错误定位，包括核细胞质运输 (NCT) 中断；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）可裂解将某些蛋白质束缚在膜上的糖基磷脂酰肌醇 (GPI) 锚。在这里，我们表明 GDE2 通过调节规范 Wnt 信号传导的动态来维持 TDP-43 核定位。 GDE2 的消除会导致成年神经元中异常持续的 Wnt 激活，这足以导致 NCT 缺陷、核孔异常和 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 TDP-43 的异常相一致。此外，GDE2 缺陷在 ALS 人类神经细胞模型中很明显，该模型显示出错误的 Wnt 激活，当受到抑制时，TDP-43 调节的基因的 mRNA 水平会增加。我们的研究确定 GDE2 是成体神经元中 Wnt 信号传导的关键生理调节因子，并强调 Wnt 通路激活是一种未受重视的机制，有助于疾病中的核细胞质运输和 TDP-43 异常。