Kumada Satoko, Uchihara Toshiki, Hayashi Masaharu, Nakamura Ayako, Kikuchi Etsuko, Mizutani Toshio, Oda Masaya
Department of Pediatrics, Metropolitan Fuchu Medical Center for Severe Motor and Intellectual Disabilities, Tokyo, Japan.
J Neuropathol Exp Neurol. 2002 Nov;61(11):984-91. doi: 10.1093/jnen/61.11.984.
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.
马里内斯科小体（MBs）是在黑质色素神经元中观察到的泛素化核内包涵体。它们的数量在衰老过程中增加，其形成被认为代表细胞对压力的反应，但并不总是与神经元变性相关。我们对强直性肌营养不良症患者大脑中丰富的MBs进行了免疫组织化学研究，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MBs与多聚谷氨酰胺蛋白之间的关系，结果表明，即使在没有多聚谷氨酰胺扩增的情况下，多聚谷氨酰胺蛋白之一ataxin-3以及一种19S蛋白酶体蛋白也优先被募集到MBs中。这表明，在MBs形成过程中，一种与多聚谷氨酰胺扩增或神经元变性无关的替代机制可能以蛋白质特异性方式将ataxin-3募集到核内包涵体中。其次，我们研究了MBs与早幼粒细胞白血病蛋白（PML）之间的关系，PML是一种与核基质相关的蛋白，通常定位于核内点状结构（PML核体），并且已知会随着多聚谷氨酰胺聚集而重新组织。在强直性肌营养不良症的黑质色素神经元中，除了点状结构外，还在其细胞核中观察到球形、半球形或棒状的PML免疫反应性结构。在老年对照和肝性脑病患者的黑质色素神经元中也观察到了类似的PML重新分布，这是另外两种形成大量MBs的情况。双重免疫荧光研究表明，在MBs形成过程中，这些PML阳性结构会随着泛素积累而发生形态变化。因此，这表明PML重新组织并不代表多聚谷氨酰胺疾病发病机制中涉及的特定核事件，而是可能在核内包涵体形成过程中作为对涉及泛素-蛋白酶体途径的各种应激的反应而普遍发生。
