打开APP

Hum Mol Genet:ALS疾病蛋白TDP-43研究取得新进展

  1. ALS疾病
  2. 新进展
  3. 研究
  4. 蛋白TDP-43

来源:遗传发育所 2014-01-02 21:35

神经细胞中蛋白质的错误聚集可导致一系列神经退行性疾病,包括脊髓侧索硬化(ALS)和额颞叶痴呆症等(FTLD)。

神经细胞中蛋白质的错误聚集可导致一系列神经退行性疾病,包括脊髓侧索硬化(ALS)和额颞叶痴呆症等(FTLD)。 突变的TDP-43常常在ALS和FTLD病人脑中聚集。TDP-43属于异种的核糖核蛋白家族,与基因转录、剪切和核小体功能相关。研究发现,突变的TDP-43对神经元和胶质细胞均可以产生毒性。然而,其作用机制尚不明确。近期,中科院遗传与发育生物学研究所李晓江组在这方面取得重要研究进展。通过在小鼠脑内纹状体中注射带有细胞特异启动子的病毒载体,他们可选择性在神经细胞和胶质细胞中表达突变的TDP-43。他们的研究发现,TDP-43更易聚集于神经元细胞中并导致神经细胞死亡、运动障碍与早期死亡。然而老龄化或抑制蛋白质降解可增加TDP-43在胶质细胞中的毒性而引起神经病理变化。该研究对由蛋白质错误聚集引发的神经退行性疾病的致病机制提出了新的解释,对治疗该类神经退行性疾病亦有指导意义。

该项工作于2013年12月30日发表在Hum. Mol. Genet.杂志上。文章的第一作者闫森,是吉林大学和美国Emory大学联合培养的博士研究生,也是遗传发育所李晓江组的客座学生。李晓江为本文的通讯作者。(生物谷Bioon.com)

生物谷推荐的英文摘要

Human Molecular Genetics         doi: 10.1093/hmg/ddt662

TDP-43 Causes Differential Pathology in Neuronal versus Glial Cells in the Mouse Brain

Yan Sen1,2,3,4, Chuan-En Wang1, Wenjie Wei1, Marta A. Gaertig1, Liangxue Lai2,3, Shihua Li1 and Xiao-Jiang Li1,4

Mutations in TAR DNA-binding protein 43 (TDP-43) are associated with familial forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although recent studies have revealed that mutant TDP-43 in neuronal and glial cells is toxic, how mutant TDP-43 causes primarily neuronal degeneration in an age-dependent manner remains unclear. Using adeno-associated virus (AAV) that expresses mutant TDP-43 (M337 V) ubiquitously, we found that mutant TDP-43 accumulates preferentially in neuronal cells in the postnatal mouse brain. We then ubiquitously or selectively expressed mutant TDP-43 in neuronal and glial cells in the striatum of adult mouse brains via stereotaxic injection of AAV vectors and found it also preferentially accumulates in neuronal cells. Expression of mutant TDP-43 in neurons in the striatum causes more severe degeneration, earlier death, and more robust symptoms in mice than expression of mutant TDP-43 in glial cells; however, aging increases the expression of mutant TDP-43 in glial cells, and expression of mutant TDP-43 in older mice caused earlier onset of phenotypes and more severe neuropathology than in younger mice. Although expression of mutant TDP-43 in glial cells via stereotaxic injection does not lead to robust neurological phenotypes, systemic inhibition of the proteasome activity via MG132 in postnatal mice could exacerbate glial TDP-43-mediated toxicity and cause mice to die earlier. Consistently, this inhibition increases the expression of mutant TDP-43 in glial cells in mouse brains. Thus, the differential accumulation of mutant TDP-43 in neuronal versus glial cells contributes to the preferential toxicity of mutant TDP-43 in neuronal cells and age-dependent pathology.

 

版权声明 本网站所有注明“来源:生物谷”或“来源:bioon”的文字、图片和音视频资料,版权均属于生物谷网站所有。非经授权,任何媒体、网站或个人不得转载,否则将追究法律责任。取得书面授权转载时,须注明“来源:生物谷”。其它来源的文章系转载文章,本网所有转载文章系出于传递更多信息之目的,转载内容不代表本站立场。不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。

87%用户都在用生物谷APP 随时阅读、评论、分享交流 请扫描二维码下载->