Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
Department of Computer Science, University of Copenhagen, Copenhagen, Denmark.
Sci Adv. 2024 May 31;10(22):eadk3229. doi: 10.1126/sciadv.adk3229.
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1 mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.
肌萎缩侧索硬化症（ALS）的特征是躯体运动神经元的进行性丧失。人们主要关注运动神经元内在特性作为退化的原因，而对脊髓中间神经元的贡献关注较少。在本工作中，我们应用转录物的多重检测和基于机器学习的图像分析，来研究 SOD1 小鼠模型中 ALS 进展过程中多种脊髓中间神经元群体的命运。分析表明，在运动神经元死亡之前，脊髓抑制性中间神经元在疾病早期就受到影响，其特征是缓慢进行性退化，而兴奋性中间神经元则在后期受到影响，退化速度较快。此外，我们还报告了抑制性和兴奋性亚群内的不同易损性。我们的研究揭示了中间神经元在 ALS 发展过程中的强烈参与，具有中间神经元特异性退化。这些观察结果表明，不同的脊髓神经元回路可能存在差异，最终可能决定运动神经元的退化。
