blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration
blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration
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DOI：
10.1523/jneurosci.23-04-01254.2003
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发表时间：
2003-02-15
影响因子：
5.3
通讯作者：
McKeown, M
中科院分区：
文献类型：
--
作者：
Finley, KD;Edeen, PT;McKeown, M
许多人类神经退行性疾病的共同特征是不溶性的含泛素的蛋白质聚集体在CNS中的积累。虽然果蝇在理解几种人类神经退行性疾病方面有所帮助，但尚未发现导致不溶性CNS蛋白质聚集体的功能丧失突变。对果蝇突变的研究可能会发现与人类退行性疾病相关的独特成分。果蝇蓝奶酪（bchs）基因定义了这样一个新的退化途径。bchs突变体具有缩短的成年寿命，并且在CNS的整个神经细胞中形成与年龄相关的蛋白质聚集体。这些包涵体含有不溶性的泛素化蛋白和淀粉样蛋白。CNS大小和形态沿着广泛的神经元凋亡的进行性丧失发生在老年bchs突变体中。BCHS蛋白在CNS神经元的细胞质中广泛表达，并且存在于轴突投射的整个长度上。BCHS的大小接近3500个氨基酸，最后1000个氨基酸由涉及囊泡运输和蛋白质加工的三个功能蛋白质基序组成。该区域与先前在人类、小鼠和线虫基因组中编码的未鉴定的蛋白质一起沿着BCHS蛋白的全长显示出惊人的同源性。果蝇和人类bchs之间的高度保守性表明，BCHS的功能途径和相关的突变表型的研究可能会提供有用的见解人类神经退行性疾病。
A common feature of many human neurodegenerative diseases is the accumulation of insoluble ubiquitin-containing protein aggregates in the CNS. Although Drosophila has been helpful in understanding several human neurodegenerative disorders, a loss-of-function mutation has not been identified that leads to insoluble CNS protein aggregates. The study of Drosophila mutations may identify unique components that are associated with human degenerative diseases. The Drosophila blue cheese (bchs) gene defines such a novel degenerative pathway. bchs mutants have a reduced adult life span with the age-dependent formation of protein aggregates throughout the neuropil of the CNS. These inclusions contain insoluble ubiquitinated proteins and amyloid precursor-like protein. Progressive loss of CNS size and morphology along with extensive neuronal apoptosis occurs in aged bchs mutants. BCHS protein is widely expressed in the cytoplasm of CNS neurons and is present over the entire length of axonal projections. BCHS is nearly 3500 amino acids in size, with the last 1000 amino acids consisting of three functional protein motifs implicated in vesicle transport and protein processing. This region along with previously unidentified proteins encoded in the human, mouse, and nematode genomes shows striking homology along the full length of the BCHS protein. The high degree of conservation between Drosophila and human bchs suggests that study of the functional pathway of BCHS and associated mutant phenotype may provide useful insights into human neurodegenerative disorders.