Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis,European Journal of Neuroscience

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Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis
European Journal of Neuroscience ( IF 2.7 ) Pub Date : 2021-08-13 , DOI: 10.1111/ejn.15422
Amanda L. Wright ₁ , Paul A. Della Gatta ₂ , Sheng Le ₁ , Britt A. Berning _{1,

3} , Prachi Mehta ₁ , Kelly R. Jacobs ₁ , Hossai Gul ₁ , Rebecca San Gil _{1,

3} , Thomas J. Hedl _{1,

3} , Winonah R. Riddell ₁ , Owen Watson ₁ , Sean S. Keating ₃ , Juliana Venturato ₃ , Roger S. Chung ₁ , Julie D. Atkin ₁ , Albert Lee ₁ , Bingyang Shi ₁ , Catherine A. Blizzard ₄ , Marco Morsch ₁ , Adam K. Walker _{1,

3}

Affiliation

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, ‘rNLS8’, mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.

中文翻译：

利鲁唑不能改善肌萎缩侧索硬化小鼠模型中由细胞质 TDP-43 引起的疾病

肌萎缩侧索硬化 (ALS) 是一种神经退行性疾病，通常用利鲁唑治疗，利鲁唑是一种小分子，可通过调节谷氨酸能神经传递起作用。然而，利鲁唑只能适度延长 ALS 患者的寿命，其确切的作用机制仍不清楚。大多数 ALS 病例的特征是细胞质 TAR DNA 结合蛋白 43 kDa (TDP-43) 的积累，了解利鲁唑在密切概括 TDP-43 病理的模型中的作用可能为改进疗法的开发提供见解。因此，我们研究了利鲁唑对雌性转基因小鼠的影响，这些小鼠在神经元中诱导表达核定位序列 (NLS)缺陷的人 TDP-43 ( NEFH -tTA/ tetO-hTDP-43ΔNLS，'rNLS8'，小鼠）。从 hTDP-43ΔNLS 表达的第一天开始，利鲁唑治疗并未改变疾病发作、体重减轻或多项运动行为任务的表现。利鲁唑处理也没有改变 TDP-43 蛋白水平、溶解度或磷酸化。尽管我们发现 rNLS8 小鼠皮层中 GluA2 和 GluA3 蛋白显着减少，但利鲁唑并没有改善这种疾病相关的分子表型。同样，利鲁唑没有改变 rNLS8 小鼠后肢肌肉的疾病相关萎缩。最后，在 rNLS8 小鼠疾病发作后开始的利鲁唑治疗同样对晚期疾病的进展或动物存活率没有影响。一起，我们证明了特定的谷氨酸能受体改变和肌肉纤维类型的变化，这让人联想到雌性 rNLS8 小鼠的 ALS，但利鲁唑对这些或任何其他疾病表型没有影响。未来可能需要针对与 TDP-43 病理学积累相关的途径来开发更好的 ALS 治疗方法。

更新日期：2021-09-21

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