Centre for the Study of Neurological Disorders, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
J Mol Neurosci. 2014 Jun;53(2):231-41. doi: 10.1007/s12031-014-0290-y. Epub 2014 Apr 4.
Endoplasmic reticulum (ER) stress has been implicated in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). MicroRNAs are small ribonucleic acids which can modulate protein expression by binding to the 3'UTR of target mRNAs. We recently identified increased miR-29a expression in response to ER stress in neurons, with members of the miR-29 family implicated in cancer and neurodegeneration. We found high expression of miR-29a in the mouse brain and spinal cord by quantitative PCR analysis and increased expression of miR-29a in the spinal cord of SOD1(G93A) transgenic mice, a mouse model of familial ALS. In situ hybridisation experiments revealed increased miR-29a expression in the lumbar spinal cord of SOD1(G93A) transgenic mice from postnatal day 70 onward when compared to wild-type mice. miR-29a knockdown was achieved in the CNS in vivo after a single intracerebroventricular injection of a miR-29a-specific antagomir. While analysis of disease progression and motor function could not identify a significant alteration in ALS disease manifestations, a trend towards increased lifespan was observed in male SOD1(G93A) mice. These findings demonstrate that miR-29a may act as a marker for disease progression in SOD1(G93A) mice, and provide first proof-of-concept for a therapeutic modulation of miR-29a function in ALS.
内质网（ER）应激与许多神经退行性疾病有关，如肌萎缩侧索硬化症（ALS）。微小 RNA 是一种小的核糖核酸，可以通过与靶 mRNA 的 3'UTR 结合来调节蛋白质表达。我们最近发现神经元中 ER 应激会引起 miR-29a 表达增加，miR-29 家族成员与癌症和神经退行性变有关。我们通过定量 PCR 分析发现 miR-29a 在小鼠大脑和脊髓中的高表达，并发现 SOD1(G93A)转基因小鼠（一种家族性 ALS 的小鼠模型）脊髓中的 miR-29a 表达增加。原位杂交实验显示，与野生型小鼠相比，SOD1(G93A)转基因小鼠从出生后 70 天开始，其腰椎脊髓中的 miR-29a 表达增加。在单次侧脑室注射 miR-29a 特异性反义寡核苷酸后，在体内实现了对 CNS 中 miR-29a 的敲低。尽管对疾病进展和运动功能的分析未能确定 ALS 疾病表现的显著改变，但在雄性 SOD1(G93A)小鼠中观察到寿命延长的趋势。这些发现表明，miR-29a 可能作为 SOD1(G93A)小鼠疾病进展的标志物，并且首次提供了在 ALS 中治疗性调节 miR-29a 功能的概念验证。
