Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin proteolipid protein.
Dominant-negative action of the jimpy mutation in mice complemented with an autosomal transgene for myelin proteolipid protein.
复制标题
小鼠中 jimpy 突变的显性失活作用与髓磷脂蛋白脂质蛋白的常染色体转基因互补。
DOI：
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发表时间：
1995
影响因子：
11.1
通讯作者：
K. Nave
中科院分区：
文献类型：
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作者：
Armin Schneider;I. Griffiths;C. Readhead;K. Nave
从无脊椎动物发育到人类退行性疾病，编码膜蛋白的基因突变与不明原因的细胞死亡有关。髓磷脂蛋白脂质蛋白 (PLP) 基因的点突变是 jimpy 小鼠少突胶质细胞死亡和髓鞘发育不良的基础，而 jimpy 小鼠是 Pelizaeus-Merzbacher 病的精确模型。为了区分 PLP 功能的丧失与错误折叠蛋白的其他影响，我们利用该基因的 X 染色体连锁，并用野生型 PLP 转基因补充 jimpy。在这种人工杂合的情况下，jimpy 突变成为遗传显性突变。在细胞水平上，尽管内源性 PLP 基因和常染色体转基因确实共表达，但少突胶质细胞的存活率几乎没有增加。在存活的少突胶质细胞中，野生型 PLP 具有功能并且在髓鞘质中可通过免疫检测。此外，压缩的髓鞘恢复了正常的周期性。这强烈表明，尽管存在功能性野生型 PLP，但错误折叠的 jimpy PLP 本身就是异常少突胶质细胞死亡的主要原因。
Mutations in genes encoding membrane proteins have been associated with cell death of unknown cause from invertebrate development to human degenerative diseases. A point mutation in the gene for myelin proteolipid protein (PLP) underlies oligodendrocyte death and dysmyelination in jimpy mice, an accurate model for Pelizaeus-Merzbacher disease. To distinguish the loss of PLP function from other effects of the misfolded protein, we took advantage of the X chromosomal linkage of the gene and have complemented jimpy with a wild-type PLP transgene. In this artificial heterozygous situation, the jimpy mutation emerged as genetically dominant. At the cellular level oligodendrocytes showed little increase in survival although endogenous PLP gene and autosomal transgene were truly coexpressed. In surviving oligodendrocytes, wild-type PLP was functional and immunodetectable in myelin. Moreover, compacted myelin sheaths regained their normal periodicity. This strongly suggests that, despite the presence of functional wild-type PLP, misfolded jimpy PLP is by itself the primary cause of abnormal oligodendrocyte death.