Huntington aggregates may not predict neuronal death in Huntington's disease.
Huntington aggregates may not predict neuronal death in Huntington's disease.
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发表时间：
1999
影响因子：
11.2
通讯作者：
S. Kuemmerle;C. Gutekunst;A. Klein;X. Li;S. H. Li;M. Beal;S. Hersch;R. Ferrante
中科院分区：
文献类型：
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作者：
S. Kuemmerle;C. Gutekunst;A. Klein;X. Li;S. H. Li;M. Beal;S. Hersch;R. Ferrante
亨廷顿病（HD）中多聚谷氨酰胺扩增导致选择性神经元变性的机制尚不清楚。我们以前曾报道，免疫组化分布的N-末端亨廷顿蛋白在HD不对应的神经病理学的严重程度，这样显着更大的亨廷顿蛋白聚集体的数量是存在于皮质内比在纹状体。我们现在显示亨廷顿蛋白聚集和纹状体神经元丢失的选择性模式之间的分离在HD中观察到。聚集体形成主要在备用的中间神经元中观察到，在脆弱的棘状纹状体神经元内很少或没有发现聚集体。多个perikaryal聚集体存在于几乎所有的皮质NADPH-黄递酶神经元和大约50%的备用NADPH-黄递酶纹状体神经元从早期级HD的情况下。在重度HD患者中，聚集物在NADPH-黄递酶神经元中以核包涵体形式更突出，核周和神经元聚集较少。与此相反，在所有HD病例中，细胞核或核周亨廷顿蛋白聚集体存在于不到4%的脆弱钙结合蛋白纹状体神经元中。这些发现支持多聚谷氨酰胺聚集可能不是细胞损失的预测因子的假设。而不是神经元死亡的预兆，突变亨廷顿蛋白聚集可能是对聚谷氨酰胺诱导的神经毒性的细胞保护机制。
The mechanism by which polyglutamine expansion in Huntington's disease (HD) results in selective neuronal degeneration remains unclear. We previously reported that the immunohistochemical distribution of N-terminal huntingtin in HD does not correspond to the severity of neuropathology, such that significantly greater numbers of huntingtin aggregates are present within the cortex than in the striatum. We now show a dissociation between huntingtin aggregation and the selective pattern of striatal neuron loss observed in HD. Aggregate formation was predominantly observed in spared interneurons, with few or no aggregates found within vulnerable spiny striatal neurons. Multiple perikaryal aggregates were present in almost all cortical NADPH-diaphorase neurons and in approximately 50% of the spared NADPH-diaphorase striatal neurons from early grade HD cases. In severe grade HD patients, aggregates were more prominent as nuclear inclusions in NADPH-diaphorase neurons, with less perikaryal and neuropil aggregation. In contrast, nuclear or perikaryal huntingtin aggregates were present in less than 4% of the vulnerable calbindin striatal neurons in all HD cases. These findings support the hypothesis that polyglutamine aggregation may not be a predictor of cell loss. Rather than a harbinger of neuronal death, mutant huntingtin aggregation may be a cytoprotective mechanism against polyglutamine-induced neurotoxicity.