Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant.
Immunoreactivity of valosin-containing protein in sporadic amyotrophic lateral sclerosis and in a case of its novel mutant.
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DOI：
10.1186/s40478-014-0172-0
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发表时间：
2014-12-10
影响因子：
7.1
通讯作者：
Takahashi R
中科院分区：
文献类型：
--
作者：
Ayaki T;Ito H;Fukushima H;Inoue T;Kondo T;Ikemoto A;Asano T;Shodai A;Fujita T;Fukui S;Morino H;Nakano S;Kusaka H;Yamashita H;Ihara M;Matsumoto R;Kawamata J;Urushitani M;Kawakami H;Takahashi R
含缬氨酸蛋白（VCP）基因的突变首次被发现可引起包涵体肌病伴早发性Paget病和额颞叶痴呆（IBMPFD）。VCP基因突变后来被报道发生在家族性肌萎缩性侧索硬化症（ALS）中。但是VCP在ALS发生的神经退行性过程中的作用仍然未知。本研究的目的是阐明VCP在散发性和VCP突变型ALS中所见的神经变性中的作用。免疫组化结果显示，与对照组相比，散发性ALS （SALS）和VCP新突变（ALS-VCP, M158V）患者脊髓运动神经元明显VCP阳性核的频率增加。在SALS患者、ALS-VCP患者和对照组中未观察到vcp阳性包涵体。ALS-VCP病例的神经病理学检查显示运动神经元丧失，布尼纳体存在，皮质脊髓束变性。在本病例中检测到的兔体证实显示免疫组织化学和超微结构特征与先前描述的相似。此外，在脊髓和髓质运动神经元中发现了TAR dna结合蛋白43 kDa （TDP-43）、磷酸化TDP-43、泛素（Ub）、p62和optinineurin免疫阳性的神经元胞浆内包体，但在新皮层中没有发现。该ALS-VCP患者基因分析证实M158V从头突变，而对照组未发现该突变；生物信息学分析显示VCP结构可能受到损伤。培养细胞的免疫细胞化学研究显示，与野生型VCP相比，转染几种突变型VCP的细胞（包括本患者的VCP）中TDP-43的细胞质易位增加。这些发现支持了VCP与SALS和家族性ALS的病理机制相关的观点，VCP突变可能通过显性-负性机制起作用。本文的在线版本（doi:10.1186/s40478-014-0172-0）包含补充材料，可供授权用户使用。
Mutations in the valosin-containing protein (VCP) gene were first found to cause inclusion- body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). Mutations in the VCP gene were later reported to occur in familial amyotrophic lateral sclerosis (ALS). But the role of VCP in the neurodegenerative processes that occur in ALS remains unknown. The purpose of the present study was to elucidate the role of VCP in the neurodegeneration seen in sporadic and VCP mutant ALS. Immunohistochemistry demonstrated that the frequency of distinct VCP-positive nuclei of spinal motor neurons of patients with sporadic ALS (SALS) and the ALS with VCP novel mutation (ALS-VCP, M158V) was increased, compared with that of the control cases. No VCP-positive inclusion bodies were observed in SALS patients, a ALS-VCP patient or in control subjects. Neuropathologic examination of the ALS-VCP case showed loss of motor neurons, the presence of Bunina bodies, and degeneration of the corticospinal tracts. Bunina bodies detected in this case were confirmed to show immunohistochemical and ultrastructural features similar to those previously described. Furthermore, neuronal intracytoplasmic inclusions immunopositive for TAR DNA-binding protein 43 kDa (TDP-43), phosphorylated TDP-43, ubiquitin (Ub), p62, and optineurin were identified in the spinal and medullary motoneurons, but not in the neocortex. Gene analysis of this ALS-VCP patient confirmed the de novo mutation of M158V, which was not found in control cases; and bioinformatics using several in silico analyses showed possible damage to the structure of VCP. Immunocytochemical study of cultured cells showed increased cytoplasmic translocation of TDP-43 in cells transfected with several mutant VCP including our patient’s compared with wild-type VCP. These findings support the idea that VCP is associated with the pathomechanism of SALS and familial ALS with a VCP mutation, presumably acting through a dominant-negative mechanism. The online version of this article (doi:10.1186/s40478-014-0172-0) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Arhzaouy K;Strucksberg KH;Tung SM;Tangavelou K;Stumpf M;Faix J;Schröder R;Clemen CS;Eichinger L
通讯作者：
Eichinger L
影响因子：
9.9
作者：
Haubenberger, D;Bittner, RE;Zimprich, A
通讯作者：
Zimprich, A
影响因子：
4.2
作者：
Bersano, Anna;Del Bo, Roberto;Corti, Stefania
通讯作者：
Corti, Stefania
影响因子：
3.4
作者：
Gidaro, Teresa;Modoni, Anna;Mirabella, Massimiliano
通讯作者：
Mirabella, Massimiliano
影响因子：
4.8
作者：
Gitcho, Michael A.;Strider, Jeffrey;Cairns, Nigel J.
通讯作者：
Cairns, Nigel J.