Department of Physiology, National University of Singapore, Singapore City, Singapore.
Life Sciences Institute, National University of Singapore, Singapore City, Singapore.
EMBO J. 2019 Mar 1;38(5). doi: 10.15252/embj.2018100989. Epub 2019 Jan 28.
Aberrant function of the RNA-binding protein TDP-43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP-43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease-associated mutation of TDP-43 all impair intracellular sorting and activity-dependent secretion of the neurotrophin brain-derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP-43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF. Human neurons derived from patient iPSCs carrying mutated TDP-43 also show altered Sortilin splicing and reduced levels of activity-dependent BDNF secretion, which can be restored by correcting the mutation. We propose that major disease phenotypes caused by aberrant TDP-43 activity may be explained by the abnormal function of a handful of critical proteins, such as BDNF.
RNA 结合蛋白 TDP-43 的功能异常与多种神经退行性疾病有关。由于其靶标众多，TDP-43 功能障碍导致疾病的机制尚不清楚。在这里，我们报告说，TDP-43 的敲低、聚集或与疾病相关的突变都通过改变转运受体 Sortilin 的剪接来损害神经营养因子脑源性神经营养因子 (BDNF) 的细胞内分拣和活性依赖性分泌。在海马 CA1 中特异性缺乏 TDP-43 的成年小鼠表现出记忆障碍和突触可塑性缺陷，通过恢复 Sortilin 剪接或细胞外 BDNF 可以挽救这些缺陷。源自携带突变 TDP-43 的患者 iPSC 的人类神经元也显示出 Sortilin 剪接的改变和活性依赖性 BDNF 分泌减少，通过纠正突变可以恢复其分泌。我们提出，由异常 TDP-43 活性引起的主要疾病表型可能是由少数关键蛋白（如 BDNF）的异常功能解释的。
