Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Department of Chemistry, Northwestern University, Evanston, Illinois, USA.
Clin Transl Med. 2021 Feb;11(2):e336. doi: 10.1002/ctm2.336.
Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs. The basis of UMN vulnerability is not fully understood, and no compound has yet been identified to improve the health of diseased UMNs: two major roadblocks for building effective treatment strategies.
Novel UMN reporter models, in which UMNs that are diseased because of misfolded superoxide dismutase protein (mSOD1) toxicity and TDP-43 pathology are labeled with eGFP expression, allow direct assessment of UMN response to compound treatment. Electron microscopy reveals very precise aspects of endoplasmic reticulum (ER) and mitochondrial damage. Administration of NU-9, a compound initially identified based on its ability to reduce mSOD1 toxicity, has profound impact on improving the health and stability of UMNs, as identified by detailed cellular and ultrastructural analyses.
Problems with mitochondria and ER are conserved in diseased UMNs among different species. NU-9 has drug-like pharmacokinetic properties. It lacks toxicity and crosses the blood brain barrier. NU-9 improves the structural integrity of mitochondria and ER, reduces levels of mSOD1, stabilizes degenerating UMN apical dendrites, improves motor behavior measured by the hanging wire test, and eliminates ongoing degeneration of UMNs that become diseased both because of mSOD1 toxicity and TDP-43 pathology, two distinct and important overarching causes of motor neuron degeneration.
Mechanism-focused and cell-based drug discovery approaches not only addressed key cellular defects responsible for UMN loss, but also identified NU-9, the first compound to improve the health of diseased UMNs, neurons that degenerate in ALS, HSP, PLS, and ALS/FTLD patients.
上运动神经元（UMN）是运动神经元回路的关键组成部分。它们的退化是遗传性痉挛性截瘫（HSP）、原发性侧索硬化症（PLS）和肌萎缩侧索硬化症（ALS）等疾病的标志。目前，尚无针对 UMN 对化合物治疗的细胞反应进行临床前检测的方法，即使是针对 UMN 疾病也是如此。UMN 易损性的基础尚未完全了解，也尚未发现能够改善患病 UMN 健康的化合物：这是构建有效治疗策略的两个主要障碍。
新型 UMN 报告模型，其中由于错误折叠的超氧化物歧化酶蛋白（mSOD1）毒性和 TDP-43 病理学而患病的 UMN 用 eGFP 表达标记，允许直接评估 UMN 对化合物治疗的反应。电子显微镜揭示了内质网（ER）和线粒体损伤的非常精确的方面。NU-9 的给药，一种最初因其降低 mSOD1 毒性的能力而被识别的化合物，对改善 UMN 的健康和稳定性有深远的影响，这是通过详细的细胞和超微结构分析确定的。
不同物种中患病 UMN 中都存在与线粒体和 ER 相关的问题。NU-9 具有类药的药代动力学特性。它没有毒性，能够穿过血脑屏障。NU-9 改善了线粒体和 ER 的结构完整性，降低了 mSOD1 的水平，稳定了退化的 UMN 顶树突，通过悬挂线测试改善了运动行为，并消除了由于 mSOD1 毒性和 TDP-43 病理学而患病的 UMN 的进行性退化，这两种疾病分别是运动神经元退化的两个重要且不同的主要原因。
以机制为重点和基于细胞的药物发现方法不仅解决了导致 UMN 丧失的关键细胞缺陷，而且还确定了 NU-9，这是第一种改善患病 UMN 健康的化合物，这些 UMN 神经元在 ALS、HSP、PLS 和 ALS/FTLD 患者中会退化。
