Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Maloney Building, 3rd Floor, 3600 Spruce Street, Philadelphia, PA, 19104-2676, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.
Acta Neuropathol Commun. 2022 May 14;10(1):75. doi: 10.1186/s40478-022-01373-0.
In the intermediate stages of amyotrophic lateral sclerosis (ALS), surviving motor neurons (MNs) that show intrinsic resistance to TDP-43 proteinopathy can partially compensate for the loss of their more disease-susceptible counterparts. Elucidating the mechanisms of this compensation may reveal approaches for attenuating motor impairment in ALS patients. In the rNLS8 mouse model of ALS-like pathology driven by doxycycline-regulated neuronal expression of human TDP-43 lacking a nuclear localization signal (hTDP-43ΔNLS), slow MNs are more resistant to disease than fast-fatigable (FF) MNs and can mediate recovery following transgene suppression. In the present study, we used a viral tracing strategy to show that these disease-resistant slow MNs sprout to reinnervate motor endplates of adjacent muscle fibers vacated by degenerated FF MNs. Moreover, we found that neuromuscular junctions within fast-twitch skeletal muscle (tibialis anterior, TA) reinnervated by SK3-positive slow MNs acquire resistance to axonal dieback when challenged with a second course of hTDP-43ΔNLS pathology. The selective resistance of reinnervated neuromuscular junctions was specifically induced by the unique pattern of reinnervation following TDP-43-induced neurodegeneration, as recovery from unilateral sciatic nerve crush did not produce motor units resistant to subsequent hTDP-43ΔNLS. Using cross-reinnervation and self-reinnervation surgery in which motor axons are disconnected from their target muscle and reconnected to a new muscle, we show that FF MNs remain hTDP-43ΔNLS-susceptible and slow MNs remain resistant, regardless of which muscle fibers they control. Collectively, these findings demonstrate that MN identity dictates the susceptibility of neuromuscular junctions to TDP-43 pathology and slow MNs can drive recovery of motor systems due to their remarkable resilience to TDP-43-driven degeneration. This study highlights a potential pathway for regaining motor function with ALS pathology in the advent of therapies that halt the underlying neurodegenerative process.
在肌萎缩侧索硬化症（ALS）的中期，表现出对 TDP-43 蛋白病固有抗性的存活运动神经元（MNs）可以部分代偿其更易患病的对应物的丧失。阐明这种代偿的机制可能会揭示减轻 ALS 患者运动障碍的方法。在由强力霉素调节神经元表达缺乏核定位信号的人 TDP-43（hTDP-43ΔNLS）驱动的 rNLS8 小鼠 ALS 样病理学模型中，慢速 MNs 比快速疲劳（FF）MNs 更能抵抗疾病，并且可以在转基因抑制后介导恢复。在本研究中，我们使用病毒追踪策略表明，这些具有疾病抗性的慢速 MNs 发芽以重新支配被退化的 FF MNs 排空的相邻肌肉纤维的运动终板。此外，我们发现由 SK3 阳性慢速 MNs 重新支配的快肌（胫骨前肌，TA）中的神经肌肉接点在受到第二个 hTDP-43ΔNLS 病理挑战时获得对轴突退变的抗性。被重新支配的神经肌肉接点的选择性抗性是由 TDP-43 诱导的神经退行性变后独特的再支配模式引起的，因为单侧坐骨神经挤压的恢复不会产生对随后的 hTDP-43ΔNLS 不敏感的运动单位。通过交叉再支配和自我再支配手术，即运动轴突与其靶肌肉分离并重新连接到新的肌肉，我们表明 FF MNs 仍然对 hTDP-43ΔNLS 敏感，而慢速 MNs 仍然具有抗性，无论它们控制哪个肌肉纤维。总的来说，这些发现表明 MN 身份决定了神经肌肉接点对 TDP-43 病理学的敏感性，并且慢速 MNs 可以由于其对 TDP-43 驱动的变性的显著弹性而驱动运动系统的恢复。这项研究强调了在潜在的神经退行性过程停止的治疗方法出现时，通过 ALS 病理学恢复运动功能的潜在途径。
