Takahashi Junko, Fujigasaki Hiroto, Iwabuchi Kiyoshi, Bruni Amalia C, Uchihara Toshiki, El Hachimi Khalid H, Stevanin Giovanni, Dürr Alexandra, Lebre Anne Sophie, Trottier Yvon, de Thé Hugues, Tanaka Junichi, Hauw Jean Jacques, Duyckaerts Charles, Brice Alexis
Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, AP-HP, Paris, France.
Neurobiol Dis. 2003 Aug;13(3):230-7. doi: 10.1016/s0969-9961(03)00080-9.
In polyglutamine diseases, accumulation in the nucleus of mutant proteins induces the formation of neuronal intranuclear inclusions (NIIs). The nucleus is compartmentalized into structural and functional domains, which are involved in NII formation. Promyelocytic leukemia protein (PML), a major component of nuclear bodies, and mSin3A, a component of the transcription co-repressor complex, were used to investigate how the intranuclear domains/sites relate to NII formation in SCA2, SCA3, SCA7, SCA17 and DRPLA brains. We demonstrate that the size of PML-positive intranuclear structures was larger in pathological brains than in control ones and that these structures contained mutant proteins. PML colocalized only with small NIIs, which maintained the ring-like structure of normal nuclear bodies. Enlarged ring-like PML-positive structures, devoid of mutant proteins, were also found and might represent structures where mutant polyglutamine proteins have been successfully processed. These data suggest that NIIs originate from nuclear bodies, where mutant proteins accumulate for degradation.
在多聚谷氨酰胺疾病中，突变蛋白在细胞核内的积累会诱导神经元核内包涵体（NIIs）的形成。细胞核被分隔成结构和功能域，这些结构和功能域参与了NII的形成。早幼粒细胞白血病蛋白（PML）是核体的主要成分，而mSin3A是转录共抑制复合物的一个成分，被用于研究核内结构域/位点与SCA2、SCA3、SCA7、SCA17和DRPLA脑内NII形成之间的关系。我们证明，在病理脑内，PML阳性核内结构的大小比对照脑内的大，并且这些结构包含突变蛋白。PML仅与小的NII共定位，这些小NII保持了正常核体的环状结构。还发现了不含突变蛋白的扩大的环状PML阳性结构，这些结构可能代表了突变多聚谷氨酰胺蛋白已被成功处理的结构。这些数据表明，NIIs起源于核体，突变蛋白在核体中积累以待降解。
