Promyelocytic Leukemia Protein Is Redistributed during the Formation of Intranuclear Inclusions Independent of Polyglutamine Expansion: An Immunohistochemical Study on Marinesco Bodies
Promyelocytic Leukemia Protein Is Redistributed during the Formation of Intranuclear Inclusions Independent of Polyglutamine Expansion: An Immunohistochemical Study on Marinesco Bodies
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早幼粒细胞白血病蛋白在核内包涵体形成过程中重新分布，与多谷氨酰胺扩增无关：Marinesco 体的免疫组织化学研究
DOI：
10.1093/jnen/61.11.984
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发表时间：
2002
期刊：
影响因子：
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通讯作者：
M. Oda
中科院分区：
文献类型：
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作者：
S. Kumada;T. Uchihara;M. Hayashi;E. Kikuchi;T. Mizutani;M. Oda
Marinesco小体（MB）是在黑质色素神经元中观察到的泛素化的核内包涵体。它们在衰老过程中数量增加，它们的形成被认为是对应激的细胞反应，但并不总是与神经元变性有关。我们对强直性肌营养不良大脑中丰富的MB进行了免疫组化研究，并将其性质与多聚谷氨酰胺疾病中的神经元核内包涵体（NIIs）进行了比较。首先，我们研究了MB和多聚谷氨酰胺蛋白之间的关系，并证明了一个多聚谷氨酰胺蛋白，共济失调蛋白-3，以及19 S蛋白酶体蛋白，优先招募到MB，即使在没有扩大的多聚谷氨酰胺。这表明在MB形成过程中与多聚谷氨酰胺扩增或神经元变性无关的另一种机制可能以蛋白质特异性方式将共济失调蛋白-3招募到核包涵体中。其次，我们研究了MB和早幼粒细胞白血病蛋白（PML）之间的关系，PML是一种核基质相关蛋白，通常定位于核内点状结构（PML核小体），并已知其与多聚谷氨酰胺聚集相关进行重组。在强直性肌营养不良的黑质色素神经元中，除了点状结构外，还观察到球形、半球形或杆状PML免疫反应结构。在老年对照组和肝性脑病病例中，也在黑质色素神经元中观察到类似的PML再分布，这是形成大量MB的其他2种情况。双重免疫荧光研究表明，这些PML阳性结构发生形态学变化与MB形成过程中的泛素积累。因此，它表明，PML重组并不代表一个特定的核事件参与的多聚谷氨酰胺疾病的发病机制，但可能通常发生在形成核内包涵体的反应，对各种压力，涉及泛素-蛋白酶体途径。
Marinesco bodies (MBs) are ubiquitinated intranuclear inclusions observed in nigral pigmented neurons. They increase in number during aging, and their formation is considered to represent a cellular reaction to stress, but is not always associated with neuronal degeneration. We conducted immunohistochemical studies on MBs abundant in myotonic dystrophy brains and compared their nature with that of neuronal intranuclear inclusions (NIIs) in polyglutamine diseases. First, we examined the relationship between MBs and polyglutamine proteins and demonstrated that one of the polyglutamine proteins, ataxin-3, as well as a 19S proteasomal protein, was preferentially recruited into MBs even in the absence of expanded polyglutamine. This indicates that an alternative mechanism during the formation of MBs that is not related to polyglutamine expansion or neuronal degeneration may recruit ataxin-3 into nuclear inclusions in a protein-specific manner. Secondly, we investigated the relationship between MBs and promyelocytic leukemia protein (PML), a nuclear matrix-associated protein that is normally localized to intranuclear punctate structures (PML nuclear bodies) and is known to reorganize itself in association with polyglutamine aggregation. In nigral pigmented neurons in myotonic dystrophy, spherical, hemispherical or rod-like PML-immunoreactive structures, in addition to punctate structures, were observed in their nuclei. Similar PML redistribution was also observed in nigral pigmented neurons in aged controls and cases of hepatic encephalopathy, 2 other conditions in which abundant MBs are formed. Double immunofluorescence study revealed that these PML-positive structures undergo morphological changes in association with ubiquitin accumulation during MB formation. It is therefore indicated that PML reorganization does not represent a specific nuclear event involved in the pathogenesis of polyglutamine diseases, but may commonly occur during the formation of intranuclear inclusions as a reaction against various stresses that involve the ubiquitin-proteasome pathway.
Akira Fuyuhiro：Bull.Chem.Soc.Jpn。
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