Regionally different immunoreactivity for Smurf2 and pSmad2/3 in TDP-43-positive inclusions of amyotrophic lateral sclerosis.
Regionally different immunoreactivity for Smurf2 and pSmad2/3 in TDP-43-positive inclusions of amyotrophic lateral sclerosis.
复制标题
肌萎缩侧索硬化症 TDP-43 阳性包涵体中 Smurf2 和 pSmad2/3 的免疫反应性存在区域差异。
DOI：
10.1111/j.1365-2990.2012.01270.x
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Kusaka H.
中科院分区：
文献类型：
--
作者：
Nakamura M;Kaneko S;Wate R;Asayama S;Nakamura Y;Fujita K;Ito H;Kusaka H.
M.Nakamura，S.Kaneko，R.Wate，S.Asayama，Y.Nakamura，K.Fujita，H.Ito和H.Kusaka(2013)神经病理学和应用神经生物学39,144-156肌萎缩侧索性硬化症TDP-43阳性包涵体中Smad2和pSmad2/3的免疫反应性区域性不同。目的：Smad泛素化调节因子-2(Smad泛素化调节因子-2)是一种E3泛素连接酶，可以与Smad蛋白相互作用，促进其泛素依赖的降解，从而控制这些信号介质的细胞水平。我们先前报道，肌萎缩侧索硬化症(ALS)患者脊髓中的反式反应DNA结合蛋白-43(TDP-43)包涵体中存在磷酸化的Smad2/3(pSmad2/3)。最近对ALS患者脊髓和脑的生化和免疫组织化学研究表明，TDP-43包涵体的成分具有区域性差异，提示不同的潜在致病过程。方法：对13例散发性肌萎缩侧索硬化症(SALS)患者的脊髓和脑组织进行免疫组织化学分析。结果：SALS患者下运动神经元中TDP-43阳性包涵体的S-2和pSmad2/3免疫阳性。此外，在携带TDP-43包涵体的细胞中还观察到核pSmad2/3免疫反应活性的丧失。相反，SALS患者脑内运动外神经元中TDP-43阳性包涵体的SMurf2和pSmad2/3均为阴性。此外，包涵体细胞核中仍有pSmad2/3的免疫反应。结论：TDP-43阳性包涵体中SMurf2和pSmad2/3表达的这种区域性差异可能是ALS患者下运动神经元丢失和皮质神经元相对较少的发病机制之一。
M. Nakamura, S. Kaneko, R. Wate, S. Asayama, Y. Nakamura, K. Fujita, H. Ito and H. Kusaka (2013)Neuropathology and Applied Neurobiology39,144–156Regionally different immunoreactivity for Smurf2 and pSmad2/3 in TDP‐43‐positive inclusions of amyotrophic lateral sclerosisAims:Smad ubiquitination regulatory factor‐2 (Smurf2), an E3 ubiquitin ligase, can interact with Smad proteins and promote their ubiquitin‐dependent degradation, thereby controlling the cellular levels of these signalling mediators. We previously reported that phosphorylated Smad2/3 (pSmad2/3) was sequestered in transactive response DNA‐binding protein‐43 (TDP‐43) inclusions in the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Recent biochemical and immunohistochemical studies on spinal cord and brain of ALS patients demonstrated that the composition of the TDP‐43 inclusions is regionally distinct, suggesting different underlying pathogenic processes. We aimed to elucidate regional differences in pathomechanisms and composition of TDP‐43 inclusions in relation to pSmad2/3 and Smurf2.Methods:The spinal cord and brain tissues of 13 sporadic ALS (SALS) patients were investigated using immunohistochemical analysis.Results:TDP‐43‐positive inclusions in lower motor neurones of SALS patients were immunopositive for Smurf2 and pSmad2/3. Multiple immunofluorescence staining for Smurf2, pSmad2/3, TDP‐43 and ubiquitin revealed co‐localization of these four proteins within the inclusions in lower motor neurones of SALS patients. Furthermore, the loss of nuclear pSmad2/3 immunoreactivity was observed in cells bearing TDP‐43 inclusions. In contrast, TDP‐43‐positive inclusions in the extramotor neurones in the brain of SALS patients were noticeably negative for Smurf2 and pSmad2/3. In addition, pSmad2/3 immunoreactivity was preserved in the nuclei of inclusion‐bearing cells.Conclusions:This regional difference in the expression of Smurf2 and pSmad2/3 within TDP‐43‐positive inclusions might be one of the pathomechanisms underlying the loss of lower motor neurones and comparatively spared cortical neurones seen in ALS.