RNA Biology ( IF 3.6 ) Pub Date : 2021-01-11 Koji Matsukawa, Michail S. Kukharsky, Sei-Kyoung Park, Sangeun Park, Naruaki Watanabe, Takeshi Iwatsubo, Tadafumi Hashimoto, Susan W. Liebman, Tatyana A. Shelkovnikova
ABSTRACT
Pathological changes involving TDP-43 protein (‘TDP-43 proteinopathy’) are typical for several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). FTLD-TDP cases are characterized by increased binding of TDP-43 to an abundant lncRNA, NEAT1, in the cortex. However it is unclear whether enhanced TDP-43-NEAT1 interaction represents a protective mechanism. We show that accumulation of human TDP-43 leads to upregulation of the constitutive NEAT1 isoform, NEAT1_1, in cultured cells and in the brains of transgenic mice. Further, we demonstrate that overexpression of NEAT1_1 ameliorates TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy. Thus, NEAT1_1 upregulation may be protective in TDP-43 proteinopathies affecting the brain. Approaches to boost NEAT1_1 expression in the CNS may prove useful in the treatment of these conditions.
中文翻译:
长非编码RNA NEAT1_1可改善TDP-43蛋白病体内模型中的TDP-43毒性
摘要
涉及TDP-43蛋白(“ TDP-43蛋白病”)的病理变化是几种神经退行性疾病的典型表现,包括额颞叶变性(FTLD)。FTLD-TDP病例的特征是TDP-43与皮质中丰富的lncRNA NEAT1的结合增加。但是,尚不清楚增强的TDP-43-NEAT1相互作用是否代表一种保护机制。我们表明,人类TDP-43的积累导致培养的细胞和转基因小鼠脑中的组成型NEAT1亚型NEAT1_1上调。此外,我们证明了NEAT1_1的过表达改善了果蝇中的TDP-43毒性。和TDP-43蛋白病的酵母模型。因此,NEAT1_1的上调可能在影响脑的TDP-43蛋白病中具有保护作用。在中枢神经系统中增强NEAT1_1表达的方法可能证明对这些疾病的治疗有用。