Different human copper-zinc superoxide dismutase mutants, SOD1G93A and SOD1H46R, exert distinct harmful effects on gross phenotype in mice.
Different human copper-zinc superoxide dismutase mutants, SOD1G93A and SOD1H46R, exert distinct harmful effects on gross phenotype in mice.
复制标题
DOI：
10.1371/journal.pone.0033409
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hadano S
中科院分区：
文献类型：
--
作者：
Pan L;Yoshii Y;Otomo A;Ogawa H;Iwasaki Y;Shang HF;Hadano S
肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一组以脑和脊髓运动神经元选择性丧失为特征的异质性致死性神经退行性疾病。建立表达突变型Cu/Zn超氧化物歧化酶（SOD 1）的转基因小鼠作为ALS模型，对ALS研究的进展产生了巨大的影响。近年来，人们认识到遗传背景和性别影响许多生理和病理表型。然而，没有系统的研究集中在使用除SOD 1G 93 A小鼠以外的ALS模型的这种影响。为了阐明遗传背景和性别对不同ALS模型的总体表型的影响，我们在这里使用两种不同遗传背景的SOD 1G 93 A和SOD 1H 46 R小鼠的同源系进行了生长曲线和寿命的比较分析; C57 BL/6 N（B6）和FVB/N（FVB）。SOD 1G 93 A和SOD 1H 46 R系之间的转基因拷贝数和它们的表达是相当的。B6同源突变体SOD 1转基因株系无论其突变和性别差异均比相应的FVB株系寿命长。值得注意的是，G93 A突变比H46 R突变引起更严重的疾病表型，其中SOD 1G 93 A小鼠，特别是在FVB背景下，表现出更广泛的体重减轻和更早的死亡。性别对存活率的影响也仅出现在FVB同源SOD 1G 93 A小鼠中。相反，与我们先前使用B6系的研究一致，在FVB同源SOD 1H 46 R中缺乏Als 2（隐性青少年ALS致病基因的小鼠同源物），而在SOD 1G 93 A中没有Als 2，小鼠导致较早死亡，这意味着遗传背景独立但突变依赖的表型修饰。这些结果表明，SOD 1G 93 A和SOD 1H 46 R介导的毒性及其相关致病途径并不相同。此外，由不同的SOD 1突变导致的与遗传背景和/或性别相关的独特的损伤作用表明在小鼠基因组中存在疾病表达的几种遗传修饰剂。
Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Creation of transgenic mice expressing mutant Cu/Zn superoxide dismutase (SOD1), as ALS models, has made an enormous impact on progress of the ALS studies. Recently, it has been recognized that genetic background and gender affect many physiological and pathological phenotypes. However, no systematic studies focusing on such effects using ALS models other than SOD1G93A mice have been conducted. To clarify the effects of genetic background and gender on gross phenotypes among different ALS models, we here conducted a comparative analysis of growth curves and lifespans using congenic lines of SOD1G93A and SOD1H46R mice on two different genetic backgrounds; C57BL/6N (B6) and FVB/N (FVB). Copy number of the transgene and their expression between SOD1G93A and SOD1H46R lines were comparable. B6 congenic mutant SOD1 transgenic lines irrespective of their mutation and gender differences lived longer than corresponding FVB lines. Notably, the G93A mutation caused severer disease phenotypes than did the H46R mutation, where SOD1G93A mice, particularly on a FVB background, showed more extensive body weight loss and earlier death. Gender effect on survival also solely emerged in FVB congenic SOD1G93A mice. Conversely, consistent with our previous study using B6 lines, lack of Als2, a murine homolog for the recessive juvenile ALS causative gene, in FVB congenic SOD1H46R, but not SOD1G93A, mice resulted in an earlier death, implying a genetic background-independent but mutation-dependent phenotypic modification. These results indicate that SOD1G93A- and SOD1H46R-mediated toxicity and their associated pathogenic pathways are not identical. Further, distinctive injurious effects resulted from different SOD1 mutations, which are associated with genetic background and/or gender, suggests the presence of several genetic modifiers of disease expression in the mouse genome.
登录
查看更多内容
影响因子：
4.4
作者：
AOKI, M;OGASAWARA, M;ABE, K
通讯作者：
ABE, K
DOI：
10.1016/j.molbrainres.2004.07.002
发表时间：
2004-11-04
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Alexander, GM;Erwin, KL;Heiman-Patterson, TD
通讯作者：
Heiman-Patterson, TD
影响因子：
14.5
作者：
HAVERKAMP, LJ;APPEL, V;APPEL, SH
通讯作者：
APPEL, SH
影响因子：
3.5
作者：
Al-Chalabi, A;Andersen, PM;Powell, JF
通讯作者：
Powell, JF
影响因子：
46.9
作者：
通讯作者：
--