Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
PLoS One. 2012;7(11):e50570. doi: 10.1371/journal.pone.0050570. Epub 2012 Nov 30.
Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt) rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcay(jit) (jittery) and Atcay(swd) (sidewinder) mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcay(ji-hes) (hesitant) line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin's physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin's role in maintaining normal neuronal function.
Caytaxin 是一种高度保守的蛋白质，由 Atcay/ATCAY 基因编码。Atcay/ATCAY 的突变已被确定为导致小脑疾病的原因，如人类罕见的遗传性疾病 Cayman 共济失调、dt 大鼠的全身性肌张力障碍以及三种共济失调小鼠品系的明显运动缺陷。虽然有几条证据表明 Caytaxin 在维持神经系统过程中起着关键作用，但 Caytaxin 的生理功能尚未完全表征。在本研究中，我们生成了针对全长 Caytaxin 的新型特异性单克隆抗体，以检查野生型和 Atcay 突变小鼠品系中的内源性 Caytaxin 表达。在两种严重共济失调的 Atcay(jit)（颤抖）和 Atcay(swd)（侧身）突变系中，Caytaxin 蛋白从脑组织中缺失，在轻度共济失调/肌张力障碍的 Atcay(ji-hes)（犹豫）系中明显减少，表明 Caytaxin 表达与疾病严重程度之间存在相关性。由于野生型人 Caytaxin 在突变侧身和颤抖小鼠中的表达挽救了共济失调表型，因此 Caytaxin 的生理功能似乎在人类和小鼠同源物之间是保守的。在多个物种和几种神经元细胞系中，Caytaxin 表达为几种蛋白异构体，其中两个最大的异构体是由保守的蛋氨酸翻译起始位点的使用引起的。本文描述的工作初步表征了 Caytaxin 蛋白及其在野生型和几种突变小鼠模型中的表达。利用这些人类 Cayman 共济失调的动物模型现在可以进行深入分析，以阐明 Caytaxin 在维持正常神经元功能中的作用。
