Linear Polyubiquitin Chain Modification of TDP-43-Positive Neuronal Cytoplasmic Inclusions in Amyotrophic Lateral Sclerosis
Linear Polyubiquitin Chain Modification of TDP-43-Positive Neuronal Cytoplasmic Inclusions in Amyotrophic Lateral Sclerosis
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DOI：
10.1093/jnen/nlz135
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发表时间：
2020-03-01
影响因子：
3.2
通讯作者：
Ito, Hidefumi
中科院分区：
文献类型：
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作者：
Nakayama, Yoshiaki;Tsuji, Kazumi;Ito, Hidefumi
含有43 kDa TAR DNA结合蛋白（TDP-43）的神经元胞质内含物（NCI）是肌萎缩侧索硬化症（ALS）的病理标志，已知是泛素化的。已经报道了八种连接类型的多聚泛素链，每种类型的链发挥不同的细胞内作用。然而，参与散发性ALS（sALS）NCIs形成的多聚泛素链的连接类型尚未阐明。我们对12例sALS患者和6例对照者的脊髓进行了免疫组织化学研究。几乎所有泛素化的NCIs都用赖氨酸48-连接的多聚泛素链（K48-Ub）免疫标记。尽管大多数NCIs对K48-Ub、线性多聚泛素链（L-Ub）和赖氨酸63-连接的多聚泛素链（K63-Ub）具有三重免疫反应性，但K48-Ub免疫阳性NCIs的薄部分未标记K63-Ub或L-Ub。我们还检测到HOIP和SHARPIN，线性泛素链组装复合物的组成部分，与L-Ub共定位在NCIs上。此外，观察到视神经磷酸酶（一种与L-U B协同作用的自噬受体）和活化的NF-κ B p65的免疫信号与L-U B在NCIs的某些部分共定位。TDP-43阳性NCI的L-Ub修饰可作为sALS中NCI的自噬清除、神经炎症和神经变性的诱导剂。
Neuronal cytoplasmic inclusions (NCIs) containing TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and are known to be ubiquitinated. Eight linkage types of polyubiquitin chains have been reported, each type of chain exerting different intracellular actions. The linkage type of polyubiquitin chain involved in the formation of NCIs in sporadic ALS (sALS), however, has not yet been elucidated. We performed immunohistochemical study of the spinal cords of 12 patients with sALS and on those of 6 control subjects. Virtually all ubiquitinated NCIs were immunolabeled with lysine 48-linked polyubiquitin chain (K48-Ub). Although the majority of NCIs were triple-immunoreactive for K48-Ub, linear polyubiquitin chain (L-Ub), and lysine 63-linked polyubiquitin chain (K63-Ub), thin parts of K48-Ub-immunopositive NCIs were not labeled for K63-Ub or L-Ub. We also detected HOIP and SHARPIN, components of linear ubiquitin chain assembly complex, colocalizing with L-Ub on NCIs. Moreover, the immunosignal of optineurin, an autophagy receptor working with L-Ub, and that of activated NF-kappa B p65, were observed to be colocalizing with L-Ub on certain parts of NCIs. The L-Ub modification of TDP-43-positive NCIs may function as an inducer of autophagic clearance of NCIs, neuroinflammation, and neurodegeneration in sALS.