Tallaksen-Greene S J, Crouse A B, Hunter J M, Detloff P J, Albin R L
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Neuroscience. 2005;131(4):843-52. doi: 10.1016/j.neuroscience.2004.10.037.
We studied the development of neuronal intranuclear inclusions (NIIs), neuropil aggregates (NAs), and expression of expanded repeat polyglutamine protein in the HdhCAG(150) knockin mouse model of Huntington's disease (HD). Diffuse nuclear localization of huntingtin protein (htt) was noted initially within striatal neurons at approximately 28 weeks, followed by the development of striatal htt immunoreactive NIIs by approximately 40 weeks. Striatal NIIs were observed initially in clusters within the matrix compartment but subsequently became diffusely distributed throughout the striatum. In the oldest animals (107 weeks), NIIs were enlarged and diffuse nuclear htt immunoreactivity reduced. Expression of ubiquitin immunoreactive NIIs paralleled but lagged behind the expression of htt immunoreactive NIIs. Abundant NIIs were found by approximately 75 weeks in layers 3 and 4 of somatosensory cortex and in layer 2 of piriform cortex. In the oldest animals, greater than 100 weeks, some NIIs were found in many brain regions. NAs were found mainly within the globus pallidus and substantia nigra, perhaps reflecting expression in striatal terminals. Cyclic AMP response element binding protein (CBP) was not localized to NIIs, arguing against gross sequestration of this transcriptionally active protein. Comparison of the relative levels of a common polyglutamine epitope in HdhCAG(150) knockin and hprtCAG(146) knockin mice shows greater expression of the polyglutamine epitope in the phenotypically less aggressive HdhCAG(150) knockin line. HdhCAG(150) knockin mice may be a model of early pathologic changes in HD.
我们研究了亨廷顿舞蹈病（HD）的HdhCAG(150)基因敲入小鼠模型中神经元核内包涵体（NIIs）、神经毡聚集物（NAs）的形成以及扩展重复多聚谷氨酰胺蛋白的表达。最初在约28周时，发现亨廷顿蛋白（htt）在纹状体神经元内呈弥漫性核定位，随后在约40周时纹状体中出现htt免疫反应性NIIs。最初在基质区的簇状结构中观察到纹状体NIIs，但随后它们在整个纹状体中呈弥漫性分布。在最老的动物（107周）中，NIIs增大，核内htt免疫反应性降低。泛素免疫反应性NIIs的表达与htt免疫反应性NIIs的表达平行，但滞后。在约75周时，在体感皮层第3和第4层以及梨状皮层第2层发现大量NIIs。在超过100周的最老动物中，在许多脑区发现了一些NIIs。NAs主要在苍白球和黑质中发现，这可能反映了其在纹状体终末的表达。环磷酸腺苷反应元件结合蛋白（CBP）未定位于NIIs，这表明该转录活性蛋白未被大量隔离。比较HdhCAG(150)基因敲入小鼠和hprtCAG(146)基因敲入小鼠中常见多聚谷氨酰胺表位的相对水平，发现在表型上攻击性较弱的HdhCAG(150)基因敲入品系中多聚谷氨酰胺表位的表达更高。HdhCAG(150)基因敲入小鼠可能是HD早期病理变化的模型。
