CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation
CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation
复制标题
DOI：
10.1093/hmg/9.13.1957
复制
发表时间：
2000-08-12
影响因子：
3.5
通讯作者：
Rouleau, GA
中科院分区：
文献类型：
--
作者：
Gaspar, C;Jannatipour, M;Rouleau, GA
马查多-约瑟夫病（Machado-Joseph disease，MJD）是由编码CAG重复序列（exp-CAG）的扩增引起的几种疾病之一。在exp-CAG相关疾病的患者和细胞模型中存在核内包涵体（intramnuclear inclusion，INI）导致了核毒性模型。眼咽肌营养不良症中也发现了类似的INI，这是由编码丙氨酸的GCG重复序列的短暂扩增引起的。在这里，我们提出，转录或翻译的移码发生在扩大CAG道的生产和积累的含聚丙氨酸的突变蛋白的结果。我们假设这些丙氨酸聚合物存款在细胞中形成INI，并可能有助于核毒性。我们的证据支持我们的假设，在淋巴母细胞从MJD患者，以及在脑桥神经元的MJD大脑和在体外细胞培养模型的疾病。我们还提供了证据表明，丙氨酸聚合物单独对细胞有害，并预测类似的致病机制可能发生在其他CAG重复疾病。
Machado-Joseph disease (MJD) is one of several disorders caused by the expansion of a coding CAG repeat (exp-CAG), The presence of intranuclear inclusions (INIs) in patients and cellular models of exp-CAG-associated diseases has lead to a nuclear toxicity model. Similar INIs are found in oculopharyngeal muscular dystrophy, which is caused by a short expansion of an alanine-encoding GCG repeat. Here we propose that transcriptional or translational frameshifts occurring within expanded CAG tracts result in the production and accumulation of polyalanine-containing mutant proteins. We hypothesize that these alanine polymers deposit in cells forming INIs and may contribute to nuclear toxicity. We show evidence that supports our hypothesis in lymphoblast cells from MJD patients, as well as in pontine neurons of MJD brain and in in vitro cell culture models of the disease. We also provide evidence that alanine polymers alone are harmful to cells and predict that a similar pathogenic mechanism may occur in the other CAG repeat disorders.