Department of Neurology, University of Ulm, Ulm, Germany.
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Exp Neurol. 2021 Jan;335:113496. doi: 10.1016/j.expneurol.2020.113496. Epub 2020 Oct 8.
Mutations in the genes TARDBP (encoding the TDP-43 protein) and TBK1 can cause familial ALS. Neuronal cytoplasmatic accumulations of the misfolded, hyperphosphorylated RNA-binding protein TDP-43 are the pathological hallmark of most ALS cases and have been suggested to be a key aspect of ALS pathogenesis. Pharmacological induction of autophagy has been shown to reduce mutant TDP-43 aggregates and alleviate motor deficits in mice. TBK1 is exemplary for several other ALS genes that regulate autophagy. Consequently, we employed double mutant mice with both a heterozygous Tbk1 deletion and transgenic expression of human TDP-43 to test the hypothesis that impaired autophagy reduces intracellular clearance of an aggregation-prone protein and enhances toxicity of mutant TDP-43. The heterozygous deletion of Tbk1 did not change expression or cellular distribution of TDP-43 protein, motor neuron loss or reactive gliosis in the spinal cord of double-mutant mice at the age of 19 months. However, it aggravated muscle denervation and, albeit to a small and variable degree, motor dysfunction in TDP-43 transgenic mice, as similarly observed in the SOD1 transgenic mouse model for ALS before. Conclusively, our findings suggest that TBK1 mutations can affect the neuromuscular synapse.
基因 TARDBP（编码 TDP-43 蛋白）和 TBK1 的突变可导致家族性 ALS。大多数 ALS 病例的病理标志是错误折叠、过度磷酸化的 RNA 结合蛋白 TDP-43 的神经元细胞质积聚，并且已被认为是 ALS 发病机制的关键方面。已表明自噬的药理学诱导可减少突变型 TDP-43 聚集并减轻小鼠的运动功能障碍。TBK1 是其他几个调节自噬的 ALS 基因的典型代表。因此，我们使用具有杂合性 Tbk1 缺失和人 TDP-43 转基因表达的双突变小鼠来检验假设，即自噬受损会减少易聚集蛋白的细胞内清除，并增强突变型 TDP-43 的毒性。在 19 个月大时，TBK1 的杂合性缺失并未改变双突变小鼠脊髓中 TDP-43 蛋白的表达或细胞分布、运动神经元丧失或反应性神经胶质增生。然而，它加剧了肌肉去神经支配，并且尽管程度较小且变化不定，但在 TDP-43 转基因小鼠中也观察到了运动功能障碍，这与 ALS 的 SOD1 转基因小鼠模型之前的观察结果相似。总之，我们的研究结果表明，TBK1 突变可影响神经肌肉突触。
