Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis
Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis
复制标题
DOI：
10.1016/j.bbadis.2006.08.002
复制
发表时间：
2006-10-01
影响因子：
6.2
通讯作者：
Mitchison, Hannah M.
中科院分区：
文献类型：
--
作者：
Cooper, Jonathan D.;Russell, Claire;Mitchison, Hannah M.
模型系统为研究nclc的分子机制提供了宝贵的工具，nclc是一种破坏性的神经退行性疾病，影响中枢神经系统相对难以接近的组织。这些模型能够评估行为，病理…细胞和分子异常，也允许开发和评估新疗法。这篇综述强调了两种可用的小型脊椎动物物种，小鼠和斑马鱼，在NCL疾病建模方面的相对优势，总结了它们在NCL研究中的作用，以及它们在开发和测试前瞻性疾病治疗方面的潜力。一组小鼠突变体可用于代表所有克隆的NCL基因疾病（组织蛋白酶D， CLN1, CLN2, CLN3, CLN5, CLN6, CLN8）。这些NCL小鼠都具有进行性神经退行性表型，与人类NCL的病理非常相似。这些模型的分析强调了NCL发病机制的几个新方面，包括神经退行性变的选择性，神经丧失之前的神经胶质反应的证据，以及确定丘脑是疾病进展早期的重要病理靶点。对小鼠的研究也强调了NCL表型的意想不到的异质性，并且已经描述了新的潜在的NCL样小鼠模型，包括组织蛋白酶、CLC氯通道和其他溶酶体相关基因突变的小鼠。这些新模型很可能为NCL疾病谱提供重要的新信息。有关NCL小鼠的信息可在NCL小鼠模型数据库（http://www.ucl.ac）中获得。英国/ ncl-models /)。斑马鱼的大部分NCL基因都有同源基因，目前正在开发NCL斑马鱼模型。该模型系统在NCL小鼠模型的基础上提供了更高的优势，包括高通量突变、药物遗传和治疗技术分析。小鼠和斑马鱼模型是NCL研究的重要共享资源，为解剖疾病机制和开发治疗方法提供了独特的可能性。(c) 2006 Elsevier B.V.版权所有
Model systems provide an invaluable tool for investigating the molecular mechanisms underlying the NCLs, devastating neurodegenerative disorders that affect the relatively inaccessible tissues of the central nervous system. These models have enabled the assessment of behavioural, pathological.. cellular, and molecular abnormalities, and also allow for development and evaluation of novel therapies. This review highlights the relative advantages of the two available small vertebrate species, the mouse and zebrafish, in modelling NCL disease, summarising how these have been useful in NCL research and their potential for the development and testing of prospective disease treatments. A panel of mouse mutants is available representing all the cloned NCL gene disorders (Cathepsin D, CLN1, CLN2, CLN3, CLN5, CLN6, CLN8). These NCL mice all have progressive neurodegenerative phenotypes that closely resemble the pathology of human NCL. The analysis of these models has highlighted several novel aspects underlying NCL pathogenesis including the selective nature of neurodegeneration, evidence for glial responses that precede neuronal loss and identification of the thalamus as an important pathological target early in disease progression. Studies in mice have also highlighted an unexpected heterogeneity underlying NCL phenotypes, and novel potential NCL-like mouse models have been described including mice with mutations in cathepsins, CLC chloride channels, and other lysosome-related genes. These new models are likely to provide significant new information on the spectrum of NCL disease. Information on NCL mice is available in the NCL Mouse Model Database (http://www.ucl.ac. uk/ncl-models/). There are homologs of most of the NCL genes in zebrafish, and NCL zebrafish models are currently in development. This model system provides additional advantages to those provided by NCL mouse models including high-throughput mutational, pharmacogenetic and therapeutic technique analyses. Mouse and zebrafish models are an important shared resource for NCL research, offering a unique possibility to dissect disease mechanisms and to develop therapeutic approaches. (c) 2006 Elsevier B.V. All rights reserved.