TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions.
TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions.
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DOI：
10.1111/nan.12485
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发表时间：
2018-12
影响因子：
5
通讯作者：
Dickson DW
中科院分区：
文献类型：
--
作者：
Koga S;Lin WL;Walton RL;Ross OA;Dickson DW
本研究旨在评估多系统萎缩（MSA）患者中反式反应DNA结合蛋白43（TDP-43）病理学的临床病理特征及其危险因素。186例尸检证实的MSA病例的杏仁核和基底前脑的石蜡包埋切片用磷酸化TDP-43的免疫组织化学进行筛选。在具有TDP-43病理学的病例中，评估了额外的脑区域。采用免疫组化、免疫荧光双染色和免疫金电镜（IEM）观察TDP-43和α-synuclein的共定位。还分析了TDP-43病理学的遗传风险因素。免疫组化显示13例（7%）TDP-43病理形态各异，如软膜下星形细胞包涵体、神经元包涵体、营养不良性神经突、血管周围包涵体和胶质细胞胞质包涵体（GCI）。多变量Logistic回归模型显示，只有高龄，而不是并发阿尔茨海默病，嗜银颗粒病或海马硬化，是MSA中TDP-43病理学的独立危险因素（OR：1.11，95%CI：1.04-1.19，P = 0.002）。TDP-43病理仅限于杏仁核的8例和扩展到海马体的2例。其余3例病例具有广泛的TDP-43病理学。免疫组织化学和免疫荧光双染色及IEM显示α-synuclein和TDP-43在颗粒包被丝的GCI中共定位。初步遗传研究未能显示TMEM 106 B或GRN的风险变体与TDP-43病理之间的关联。TDP-43病理在MSA中是罕见的，主要发生在内侧颞叶。高龄是MSA中TDP-43病理的危险因素。TDP-43和α-突触核蛋白在GCI中的共定位表明这两种分子之间可能存在直接相互作用。
This study aimed to assess clinicopathologic features of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and its risk factors in multiple system atrophy (MSA). Paraffin-embedded sections of the amygdala and basal forebrain from 186 autopsy-confirmed MSA cases were screened with immunohistochemistry for phospho-TDP-43. In cases having TDP-43 pathology, additional brain regions were assessed. Immunohistochemical and immunofluorescence double-staining and immunogold electron microscopy (IEM) were performed to evaluate colocalization of TDP-43 and α-synuclein. Genetic risk factors for TDP-43 pathology were also analysed. Immunohistochemistry showed various morphologies of TDP-43 pathology in 13 cases (7%), such as subpial astrocytic inclusions, neuronal inclusions, dystrophic neurites, perivascular inclusions, and glial cytoplasmic inclusions (GCIs). Multivariable logistic regression models revealed that only advanced age, but not concurrent Alzheimer's disease, argyrophilic grain disease or hippocampal sclerosis, was an independent risk factor for TDP-43 pathology in MSA (OR: 1.11, 95% CI: 1.04–1.19, P = 0.002). TDP-43 pathology was restricted to the amygdala in eight cases and extended to the hippocampus in two cases. The remaining three cases had widespread TDP-43 pathology. Immunohistochemical and immunofluorescence double-staining and IEM revealed colocalization of α-synuclein and TDP-43 in GCIs with granule-coated filaments. Pilot genetic studies failed to show associations between risk variants of TMEM106B or GRN and TDP-43 pathology. TDP-43 pathology is rare in MSA and occurs mainly in the medial temporal lobe. Advanced age is a risk factor for TDP-43 pathology in MSA. Colocalization of TDP-43 and α-synuclein in GCIs suggests possible direct interaction between the two molecules.
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影响因子：
11.2
作者：
Josephs KA;Whitwell JL;Tosakulwong N;Weigand SD;Murray ME;Liesinger AM;Petrucelli L;Senjem ML;Ivnik RJ;Parisi JE;Petersen RC;Dickson DW
通讯作者：
Dickson DW
对医疗统计信息的自由使用的易于使用的软件“ EZR”的调查。
影响因子：
4.8
作者：
Kanda Y
通讯作者：
Kanda Y
影响因子：
6
作者：
Cairns, Nigel J.;Neumann, Manuela;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
12.7
作者：
Arai, Tetsuaki;Mackenzie, Ian R. A.;Akiyama, Haruhiko
通讯作者：
Akiyama, Haruhiko
影响因子：
8.6
作者：
Koga, Shunsuke;Sanchez-Contreras, Monica;Dickson, Dennis W.
通讯作者：
Dickson, Dennis W.