Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
FASEB J. 2019 Oct;33(10):11223-11234. doi: 10.1096/fj.201900830R. Epub 2019 Jul 17.
Recent reports attribute numerous regulatory functions to the nuclear paraspeckle-forming long noncoding RNA, nuclear enriched assembly transcript 1 (NEAT1), but the implications of its involvement in Parkinson's disease (PD) remain controversial. To address this issue, we assessed NEAT1 expression levels and cell type patterns in the substantia nigra (SN) from 53 donors with and without PD, as well as in interference tissue culture tests followed by multiple in-house and web-available models of PD. PCR quantification identified elevated levels of NEAT1 expression in the PD SN compared with control brains, an elevation that was reproducible across a multitude of disease models. RNA hybridization supported neuron-specific formation of NEAT1-based paraspeckles at the SN and demonstrated coincreases of NEAT1 and paraspeckles in cultured cells under paraquat (PQ)-induced oxidative stress. Furthermore, neuroprotective agents, including fenofibrate and simvastatin, induced NEAT1 up-regulation, whereas RNA interference-mediated depletion of NEAT1 exacerbated death of PQ-exposed cells in a leucine-rich repeat kinase 2-mediated manner. Our findings highlight a novel protective role for NEAT1 in PD and suggest a previously unknown mechanism for the neuroprotective traits of widely used preventive therapeutics.-Simchovitz, A., Hanan, M., Niederhoffer, N., Madrer, N., Yayon, N., Bennett, E. R., Greenberg, D. S., Kadener, S., Soreq, H. NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug-inducible neuroprotection from oxidative stress.
最近的报告将许多调节功能归因于核核仁旁形成长非编码 RNA，核富集组装转录物 1（NEAT1），但它参与帕金森病（PD）的影响仍存在争议。为了解决这个问题，我们评估了来自 53 名有和没有 PD 的供体的黑质（SN）中的 NEAT1 表达水平和细胞类型模式，以及随后的干扰组织培养测试以及多个内部和网络提供的 PD 模型。PCR 定量鉴定出 PD SN 中 NEAT1 的表达水平升高与对照大脑相比，这种升高在多种疾病模型中具有可重复性。RNA 杂交支持在 SN 中神经元特异性形成基于 NEAT1 的核仁旁斑点，并证明在百草枯（PQ）诱导的氧化应激下培养细胞中 NEAT1 和核仁旁斑点的共同增加。此外，神经保护剂，包括非诺贝特和辛伐他汀，诱导 NEAT1 的上调，而 RNA 干扰介导的 NEAT1 耗竭以亮氨酸丰富重复激酶 2（LRRK2）介导的方式加剧了 PQ 暴露细胞的死亡。我们的研究结果强调了 NEAT1 在 PD 中的新的保护作用，并提出了广泛使用的预防性治疗药物的神经保护特性的未知机制。-Simchovitz，A.，Hanam，M.，Niederhoffer，N.，Madrer，N.，Yayon，N.，Bennett，E. R.，Greenberg，D. S.，Kadener，S.，Soreq，H. NEAT1 在帕金森病黑质中过度表达，并赋予药物诱导的氧化应激神经保护作用。
