Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration
Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration
复制标题
进行性核上性麻痹和皮质基底节变性中的运动神经元 TDP-43 蛋白病
作者：
Riku Yuichi;Iwasaki Yasushi;Ishigaki Shinsuke;Akagi Akio;Hasegawa Masato;Nishioka Kenya;Li Yuanzhe;Riku Miho;Ikeuchi Takeshi;Fujioka Yusuke;Miyahara Hiroaki;Sone Jun;Hattori Nobutaka;Yoshida Mari;Katsuno Masahisa;Sobue Gen
在肌萎缩侧索硬化症的病例中，TDP-43从细胞核错误定位并聚集在受影响神经元的细胞质内。在非肌萎缩侧索硬化症条件下的脑组织中也发现了TDP-43病理学，表明TDP-43相关的肌萎缩侧索硬化症和各种神经系统疾病之间的机制联系。本研究旨在评估TDP-43在tau蛋白病的脊髓运动神经元中的病理学。我们检查了106例连续尸检病例的脊髓，其中进行性核上性麻痹（n= 26），皮质基底节变性（n= 12），球状胶质tau蛋白病（n= 5），阿尔茨海默病（n= 21）或皮克病（n= 6）和神经健康对照（n= 36）。10例进行性核上性麻痹病例（38%）和7例皮质基底节变性病例（58%）显示TDP-43在脊髓运动神经元中的错误定位和胞质聚集，这在颈髓中突出。TDP-43聚集体呈束状、圆形、颗粒状或点状，并含有不溶性C-末端片段，显示肌萎缩侧索硬化或额颞叶变性的印迹模式。下运动神经元也表现出胱抑素-C聚集体，虽然Bunina体中没有苏木精-伊红染色。脊髓TDP-43病理学通常与初级运动皮质的TDP-43病理学相关。TDP-43和四重复（4 R）-tau聚集体在颈髓中的严重程度之间呈正相关。TDP-43和4 R-tau聚集体负荷与前角中的小胶质细胞负荷呈正相关。脊髓运动神经元的TDP-43病理学不以年龄依赖性方式发展，并且在阿尔茨海默病、皮克病、球状胶质tau蛋白病和对照组中未发现。接下来，我们评估了SFPQ在脊髓运动神经元中的表达; SFPQ是最近确定的肌萎缩侧索硬化/额颞叶变性发病机制的调节剂，并且还报道了SFPQ和FUS之间的相互作用调节MAPT外显子10的剪接。免疫荧光和邻近连接试验显示，进行性核上性麻痹、皮质基底节变性和肌萎缩侧索硬化症-TDP病例的神经元核中的SFPQ/FUS相互作用发生改变，但阿尔茨海默病、皮克病和球状神经胶质tau蛋白病病例中没有。此外，在进行性核上性麻痹和皮质基底节变性病例中，SFPQ表达在含有TDP-43或4 R-tau聚集体的神经元中耗尽。我们的研究结果表明，进行性核上性麻痹和皮质基底节变性可能具有系统性运动神经元TDP-43蛋白病的性质，这表明与肌萎缩侧索硬化症TDP的机制联系。SFPQ功能障碍，所产生的改变与FUS的相互作用，可能是一个共同的途径的候选人。
TDP-43 is mislocalized from the nucleus and aggregates within the cytoplasm of affected neurons in cases of amyotrophic lateral sclerosis. TDP-43 pathology has also been found in brain tissues under non-amyotrophic lateral sclerosis conditions, suggesting mechanistic links between TDP-43-related amyotrophic lateral sclerosis and various neurological disorders. This study aimed to assess TDP-43 pathology in the spinal cord motor neurons of tauopathies. We examined 106 spinal cords from consecutively autopsied cases with progressive supranuclear palsy (n= 26), corticobasal degeneration (n= 12), globular glial tauopathy (n= 5), Alzheimer’s disease (n= 21) or Pick's disease (n= 6) and neurologically healthy controls (n= 36). Ten of the progressive supranuclear palsy cases (38%) and seven of the corticobasal degeneration cases (58%) showed mislocalization and cytoplasmic aggregation of TDP-43 in spinal cord motor neurons, which was prominent in the cervical cord. TDP-43 aggregates were found to be skein-like, round-shaped, granular or dot-like and contained insoluble C-terminal fragments showing blotting pattern of amyotrophic lateral sclerosis or frontotemporal lobar degeneration. The lower motor neurons also showed cystatin-C aggregates, although Bunina bodies were absent in haematoxylin-eosin staining. The spinal cord TDP-43 pathology was often associated with TDP-43 pathology of the primary motor cortex. Positive correlations were shown between the severities of TDP-43 and four-repeat (4R)-tau aggregates in the cervical cord. TDP-43 and 4R-tau aggregates burdens positively correlated with microglial burden in anterior horn. TDP-43 pathology of spinal cord motor neuron did not develop in an age-dependent manner and was not found in the Alzheimer’s disease, Pick's disease, globular glial tauopathy and control groups. Next, we assessed SFPQ expression in spinal cord motor neurons; SFPQ is a recently identified regulator of amyotrophic lateral sclerosis/frontotemporal lobar degeneration pathogenesis, and it is also reported that interaction between SFPQ and FUS regulates splicing ofMAPTexon 10. Immunofluorescent and proximity-ligation assays revealed altered SFPQ/FUS-interactions in the neuronal nuclei of progressive supranuclear palsy, corticobasal degeneration and amyotrophic lateral sclerosis-TDP cases but not in Alzheimer’s disease, Pick's disease and globular glial tauopathy cases. Moreover, SFPQ expression was depleted in neurons containing TDP-43 or 4R-tau aggregates of progressive supranuclear palsy and corticobasal degeneration cases. Our results indicate that progressive supranuclear palsy and corticobasal degeneration may have properties of systematic motor neuron TDP-43 proteinopathy, suggesting mechanistic links with amyotrophic lateral sclerosis-TDP. SFPQ dysfunction, arising from altered interaction with FUS, may be a candidate of the common pathway.