Small molecule modulators of lncRNA NEAT1_2: A novel approach to enhancing the endogenous neuroprotective response in amyotrophic lateral sclerosis

肌萎缩侧索硬化症(ALS)是一种运动神经元病，控制肌肉的神经细胞(运动神经元)退化死亡。这会导致患者进行日常活动的能力下降，负责呼吸的肌肉逐渐丧失功能，最终导致患者死于呼吸衰竭。尽管在大多数情况下，ALS的病因尚不清楚，但在少数患者中，这种疾病是由编码各种不同蛋白质的基因变化引起的。然而，尽管肌萎缩侧索硬化症的病因不同，幸存的运动神经元的一个共同特征是在核内存在被称为副视皮层的结构。这些结构被认为是对神经元应激的正常反应，因此被认为具有神经保护作用。因此，假设增加副脑的数量应该会增强对细胞应激源的保护，从而减少ALS运动神经元的死亡。神经保护副脑的一个中心成分是NEAT1_2，这是一种不编码任何蛋白质的RNA(称为长非编码RNA或lncRNA)。这种分子就像一块磁铁，吸引附着在NEAT1_2上的蛋白质形成成熟的副斑点。我们的假设是，如果我们能够增加NEAT1_2的含量，那么ALS运动神经元的类视皮层数量和由此产生的神经保护作用也将增加。RNA分子通常是相对无形状的，这意味着很难识别能够与其结合并改变其功能的化合物。然而，NEAT1_2含有一个高度结构化的区域，称为‘三螺旋’，它服从于小分子的结合。化合物与这样的结构区域的结合是调节RNAs功能的一种非常创新的方法，最近在另一种lncRNA MALAT1中证明了这一策略可以成功。在本项目中，我们旨在寻找与NEAT1_2的三螺旋结合的化合物，以稳定该lncRNA。这应该会增加运动神经元核中NEAT1_2的数量，这将反过来在ALS和潜在的其他神经退行性疾病中形成更多的神经保护性副脑，从而定义一类新的神经保护和疾病修改药物。

Amyotrophic lateral sclerosis (ALS) is a type of motor neuron disease in which the nerve cells (motor neurons) that control the muscles degenerate and die. This causes in a decline in the ability of the patient to conduct everyday activities, with the progressive loss of function of the muscles responsible for breathing ultimately resulting in the patient dying of respiratory failure. Although in most cases the cause of ALS is unknown, in a small number of patients, the disease is caused by changes in the genes that encode a variety of different proteins. However, despite the different causes of ALS, a common feature in surviving motor neurons is the presence within the nucleus of structures called paraspeckles. These structures are thought to be a normal response to neuronal stress and are therefore considered to be neuroprotective. Consequently, it is hypothesised that increasing the number of paraspeckles should enhance the protection against the cellular stressors and thereby reduce the death of motor neurons in ALS.A central component of the neuroprotective paraspeckle is NEAT1_2, an RNA that does not code for any protein (known as a long non-coding RNA or lncRNA). This molecule acts as a magnet which attracts proteins which stick to NEAT1_2 to form the mature paraspeckle. Our hypothesis is that if we can increase the amount of NEAT1_2 then the number of paraspeckles and resultant neuroprotective effects in ALS motor neurons will also be increased. RNA molecules are generally relatively shapeless which means it is difficult to identify compounds that can bind to them and alter their function. However, NEAT1_2 contains a highly structured region called the 'triple helix' which is amenable to the binding of small molecules. The binding of compounds to such structured regions is a very innovative approach to regulating the function of RNAs, and validation that this strategy can be successful has recently been demonstrated with another lncRNA, MALAT1. In this project we aim to identify compounds that bind to the triple helix of NEAT1_2 with the aim of stabilising this lncRNA. This should increase the amount of NEAT1_2 in the nuclei of motor neurons which will in turn seed the formation of an increased number of neuroprotective paraspeckles in ALS and, potentially, other neurodegenerative disorders, thereby defining a new class of neuroprotective, disease-modifying drugs.