Wanderer Jonathan, Morton A Jennifer
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
Histochem Cell Biol. 2007 May;127(5):473-84. doi: 10.1007/s00418-007-0272-z. Epub 2007 Feb 7.
The histological hallmark feature of Huntington's disease (HD) and other polyglutamine repeat diseases is the presence of intracellular inclusions. Much work has been devoted to trying to determine the relationship between inclusion formation and neuronal injury. However, little attention has been paid to the variability and characteristics of inclusions themselves. Here, we characterize the morphological and biochemical composition of inclusions in both a transgenic mouse model (R6/2 line) and an inducible cell culture model of HD (iPC12Q74). We identified several morphologically distinct kinds of inclusions in different locations (nuclei, cytoplasm and cellular processes). Ubiquitin colocalized completely with all of these inclusions in both the iPC12Q72 and R6/2 models. In the inclusions in iPC12Q74 cells, the 20S and 11S proteasome subunits colocalized variably, and the 19S subunit did not colocalize at all. In inclusions in R6/2 mouse neurons, the 20S subunit colocalized completely, but neither the 11S nor the 19S subunits colocalized at all. While the role of inclusions in the pathogenesis of HD continues to be debated, we suggest that the content and structure of inclusions vary considerably, not only from cell to cell but even within individual cells. Their role in the pathogenesis of HD is likely to depend on their location as well as their composition.
亨廷顿舞蹈病（HD）及其他多聚谷氨酰胺重复疾病的组织学标志性特征是细胞内包含物的存在。大量研究致力于确定包含物形成与神经元损伤之间的关系。然而，对于包含物自身的变异性和特征却很少有人关注。在此，我们对转基因小鼠模型（R6/2品系）和HD诱导性细胞培养模型（iPC12Q74）中包含物的形态和生化组成进行了表征。我们在不同位置（细胞核、细胞质和细胞突起）鉴定出几种形态上不同的包含物。在iPC12Q72和R6/2模型中，泛素与所有这些包含物完全共定位。在iPC12Q74细胞的包含物中，20S和11S蛋白酶体亚基的共定位情况各异，而19S亚基根本不共定位。在R6/2小鼠神经元的包含物中，20S亚基完全共定位，但11S和19S亚基都根本不共定位。虽然包含物在HD发病机制中的作用仍存在争议，但我们认为，包含物的含量和结构差异很大，不仅在细胞之间，甚至在单个细胞内也是如此。它们在HD发病机制中的作用可能取决于其位置以及组成。
