Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein

被引:27
作者
Tagawa, K
Hoshino, M
Okuda, T
Ueda, H
Hayashi, H
Engemann, S
Okado, H
Ichikawa, M
Wanker, EE
Okazawa, H
机构
[1] Tokyo Metropolitan Inst Neurosci, Dept Mol Therapeut, Tokyo 1838526, Japan
[2] Tokyo Metropolitan Inst Neurosci, Dept Dev Morphol, Tokyo 1838526, Japan
[3] Tokyo Metropolitan Inst Neurosci, Dept Mol Neurophysiol, Tokyo 1838526, Japan
[4] Max Delbruck Ctr Mol Med, Berlin, Germany
[5] Japan Sci & Technol Corp, CREST, Kawagoe, Saitama, Japan
[6] Japan Sci & Technol Corp, PRESTO, Kawagoe, Saitama, Japan
[7] Tokyo Med & Dent Univ, Dept Neuropathol, Med Res Inst, Bunkyo Ku, Tokyo, Japan
关键词
huntingtin; Huntington's disease; inclusion body; neurodegeneration; polyglutamine; transcription;
D O I
10.1111/j.1471-4159.2004.02372.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:974 / 987
页数:14
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