Department of Neuropathology, Graduate School of Medicine.
Hum Mol Genet. 2013 Nov 15;22(22):4474-84. doi: 10.1093/hmg/ddt296. Epub 2013 Jun 25.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss of motor neurons. The discovery of mutations in the gene encoding an RNA-binding protein, TAR DNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities in RNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resulted in vacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated by mutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy.
肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元进行性和选择性丧失。在家族性 ALS 中发现编码 RNA 结合蛋白 TAR DNA 结合蛋白 43 kD（TDP-43）的基因突变，强烈提示 RNA 处理异常在 ALS 的发病机制中起作用，尽管 TDP-43 导致神经退行性变的确切机制仍不清楚。为了阐明 TDP-43 引起的变性机制，我们在视网膜光感受器神经元中表达了一系列经过系统修饰的人 TDP-43 基因的转基因黑腹果蝇。野生型 TDP-43 的过表达导致光感受器神经元的空泡变性，伴有视网膜变薄，与家族性 ALS 相关的 TDP-43 突变或破坏其核定位信号（NLS）显著加剧了这种变性。值得注意的是，通过添加一个突变或缺失 RNA 识别基序（该基序会破坏 TDP-43 的 RNA 结合能力），这些变性表型完全恢复正常。总的来说，我们的结果表明，RNA 结合是 TDP-43 过表达引起神经退行性变的关键，并且 RNA 处理异常可能对 TDP-43 蛋白病的发病机制至关重要。
