Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3052, Australia.
Cereb Cortex. 2017 Jul 1;27(7):3630-3647. doi: 10.1093/cercor/bhw185.
TDP-43 is a major protein component of pathological neuronal inclusions that are present in frontotemporal dementia and amyotrophic lateral sclerosis. We report that TDP-43 plays an important role in dendritic spine formation in the cortex. The density of spines on YFP+ pyramidal neurons in both the motor and somatosensory cortex of Thy1-YFP mice, increased significantly from postnatal day 30 (P30), to peak at P60, before being pruned by P90. By comparison, dendritic spine density was significantly reduced in the motor cortex of Thy1-YFP::TDP-43A315T transgenic mice prior to symptom onset (P60), and in the motor and somatosensory cortex at symptom onset (P90). Morphological spine-type analysis revealed that there was a significant impairment in the development of basal mushroom spines in the motor cortex of Thy1-YFP::TDP-43A315T mice compared to Thy1-YFP control. Furthermore, reductions in spine density corresponded to mislocalisation of TDP-43 immunoreactivity and lowered efficacy of synaptic transmission as determined by electrophysiology at P60. We conclude that mutated TDP-43 has a significant pathological effect at the dendritic spine that is associated with attenuated neural transmission.
TDP-43 是存在于额颞叶痴呆和肌萎缩性侧索硬化症中的病理性神经元包含物的主要蛋白质成分。我们报告称，TDP-43 在皮质中的树突棘形成中发挥重要作用。在 Thy1-YFP 小鼠的运动和体感皮层中的 YFP+ 锥体神经元上，棘密度从出生后 30 天（P30）开始显著增加，在 P60 时达到峰值，然后在 P90 时被修剪。相比之下，在发病前（P60）和发病时（P90），Thy1-YFP::TDP-43A315T 转基因小鼠的运动皮层中的树突棘密度显著降低。形态学棘型分析显示，与 Thy1-YFP 对照相比，Thy1-YFP::TDP-43A315T 小鼠运动皮层中的基底蘑菇棘的发育明显受损。此外，在 P60 时通过电生理学确定的突触传递效率降低，与 TDP-43 免疫反应性的定位错误和树突棘密度降低相对应。我们的结论是，突变型 TDP-43 在与减弱的神经传递相关的树突棘上具有显著的病理性影响。
