Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
Nat Neurosci. 2019 Feb;22(2):180-190. doi: 10.1038/s41593-018-0293-z. Epub 2019 Jan 14.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS-FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）与核转录反应 DNA 结合蛋白 43（TDP-43）的缺失有关。在这里，我们发现 TDP-43 调节神经元生长相关因子 stathmin-2 的表达。TDP-43 水平降低，减少了其与 stathmin-2 前信使 RNA 第一内含子内位点的结合，揭示了一个隐藏的多聚腺苷酸化位点，其利用产生截断的、无功能的 mRNA。在表达导致 ALS 的 TDP-43 突变的患者成纤维细胞转分化的神经元中、在散发性 ALS 和 C9orf72 基因中 GGGGCC 重复扩展的家族性 ALS 的运动皮层和脊髓运动神经元中以及在诱导多能干细胞（iPSC）衍生的运动神经元中发现 stathmin-2 的表达减少，这些神经元中 TDP-43 被耗尽。值得注意的是，虽然 TDP-43 的减少被证明抑制了 iPSC 衍生的运动神经元的轴突再生，但 stathmin-2 的表达恢复挽救了轴突再生能力。因此，过早的多聚腺苷酸化介导的 stathmin-2 减少是 ALS-FTD 的一个标志，它将核 TDP-43 功能的降低与增强的神经元易感性功能联系起来。
