Takahashi H
Department of Pathology, Niigata University.
Rinsho Shinkeigaku. 1999 Dec;39(12):1279-81.
A new entity--the conformational disease--an otherwise diverse group of disorders, includes several currently incurable brain diseases such as Alzheimer's disease, prion encephalopathies and inherited polyglutamine diseases (PGDs) in which it is proposed that conformational changes in certain proteins and their subsequent aggregation represent the common pathogenic mechanism of neurodegeneration. In several PGDs including dentatorubral-pallidoluysian atrophy (DRPLA), neuronal intranuclear inclusions (NIIs) have been identified. Here I describe our recent studies on DRPLA. Formation of both intranuclear and intracytoplasmic inclusions by mutant DRPLA proteins with an expanded polyglutamine stretch was demonstrated in an in vitro experiment. Inclusion-containing non-brain cells were found to undergo apoptosis. In human DRPLA, similar intranuclear inclusions were detected in neurons in various brain regions. However, intracytoplasmic inclusions were found exclusively in neurons in the cerebeller dentate nucleus. The pontine nuclei neurons with NIIs, for instance, appeared to be small (atrophic), but healthy. The question of whether these NIIs actually kill brain cells in the human disease, remains unclear. Recently, NIIs were studied immunohistochemically using antibodies against transcription factors, and were found to contain TAFIIp130, Sp 1 and CREB-1. These results are of great interest when considering not only how the neurodegenerative mechanism progresses but also why the inclusions are located in nuclei in PGDs. Finally, Tsuji and colleagues recently established a transgenic mouse model of DRPLA. In these mice, NIIs, which were identical to those seen in the human disease, were confirmed in various brain regions. Further detailed studies of this model will contribute to a better understanding of the formation of neuronal inclusions and neurodegeneration in DRPLA.
一种新的疾病类型——构象性疾病，这是一组原本多样的病症，包括几种目前无法治愈的脑部疾病，如阿尔茨海默病、朊病毒脑病和遗传性多聚谷氨酰胺疾病（PGDs），据推测，某些蛋白质的构象变化及其随后的聚集是神经退行性变的共同致病机制。在包括齿状核红核苍白球路易体萎缩症（DRPLA）在内的几种PGDs中，已经发现了神经元核内包涵体（NIIs）。在此，我描述我们最近对DRPLA的研究。在体外实验中证实了具有扩展多聚谷氨酰胺片段的突变型DRPLA蛋白可形成核内和胞质内包涵体。发现含有包涵体的非脑细胞会发生凋亡。在人类DRPLA中，在不同脑区的神经元中检测到了类似的核内包涵体。然而，胞质内包涵体仅在小脑齿状核的神经元中发现。例如，具有NIIs的脑桥核神经元似乎较小（萎缩），但健康。这些NIIs在人类疾病中是否真的会杀死脑细胞，这个问题仍不清楚。最近，使用针对转录因子的抗体对NIIs进行了免疫组织化学研究，发现它们含有TAFIIp130、Sp1和CREB-1。当不仅考虑神经退行性变机制如何进展，而且考虑为什么包涵体在PGDs中位于细胞核时，这些结果非常有趣。最后，Tsuji及其同事最近建立了DRPLA的转基因小鼠模型。在这些小鼠中，在不同脑区证实了与人类疾病中所见相同的NIIs。对该模型的进一步详细研究将有助于更好地理解DRPLA中神经元包涵体的形成和神经退行性变。
