Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein
Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein
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DOI：
10.1111/j.1471-4159.2004.02372.x
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发表时间：
2004-05
影响因子：
4.7
通讯作者：
K. Tagawa;M. Hoshino;T. Okuda;H. Ueda;H. Hayashi;S. Engemann;H. Okado;M. Ichikawa;E. Wanker;H. Okazawa
中科院分区：
文献类型：
--
作者：
K. Tagawa;M. Hoshino;T. Okuda;H. Ueda;H. Hayashi;S. Engemann;H. Okado;M. Ichikawa;E. Wanker;H. Okazawa
疾病蛋白的聚集被认为是多聚谷氨酰胺疾病病理学中的中心事件，而聚集与神经元死亡之间的关系仍然存在争议。我们通过在从大鼠大脑皮层、纹状体或小脑制备的不同类型的神经元中表达突变亨廷顿蛋白（htt）来研究这个问题。包涵体在不同类型的原代神经元中的分布模式不尽相同。在感染后第2天，细胞质内含物是占主导地位的皮质和纹状体神经元，而在第4天的核内含物的比例超过了细胞质内含物。同时，核包涵体总是主要存在于小脑神经元中。包涵体阳性细胞的百分比在小脑神经元中最高，而突变体htt在皮质神经元中诱导细胞死亡最显著。由于我们的系统使用htt外显子1蛋白，因此聚集的发生独立于全长htt的切割，我们的观察表明聚集过程在不同的神经元中是不同的。大多数含有细胞内（细胞核或细胞质）聚集体的神经元是活的。我们的研究结果表明，突变htt聚集的过程，而不是由此产生的包涵体是神经元细胞死亡的关键。
Aggregation of disease proteins is believed to be a central event in the pathology of polyglutamine diseases, whereas the relationship between aggregation and neuronal death remains controversial. We investigated this question by expressing mutant huntingtin (htt) with a defective adenovirus in different types of neurons prepared from rat cerebral cortex, striatum or cerebellum. The distribution pattern of inclusions is not identical among different types of primary neurons. On day 2 after infection, cytoplasmic inclusions are dominant in cortical and striatal neurons, whereas at day 4 the ratio of nuclear inclusions overtakes that of cytoplasmic inclusions. Meanwhile, nuclear inclusions are always predominantly present in cerebellar neurons. The percentage of inclusion‐positive cells is highest in cerebellar neurons, whereas mutant htt induces cell death most remarkably in cortical neurons. As our system uses htt exon 1 protein and thus aggregation occurs independently from cleavage of the full‐length htt, our observations indicate that the aggregation process is distinct among different neurons. Most of the neurons containing intracellular (either nuclear or cytoplasmic) aggregates are viable. Our findings suggest that the process of mutant htt aggregation rather than the resulting inclusion body is critical for neuronal cell death.