Division of Anatomical Science, Department of Functional Morphology, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan.
Laboratory of Neurobiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Mol Cell Neurosci. 2022 Jul;121:103745. doi: 10.1016/j.mcn.2022.103745. Epub 2022 Jun 2.
Microgravity (MG) exposure and motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), lead to motor deficits, including muscle atrophy and loss of neuronal activity. Abnormalities in motor neurons and muscles caused by MG exposure can be recovered by subsequent ground exercise. In contrast, the degeneration that occurs in ALS is irreversible. A common phenotype between MG exposure and ALS pathology is motor system abnormality, but the causes may be different. In this study, to elucidate the motor system that is affected by each condition, we investigated the effects of MG and the human SOD1 ALS mutation on gene expression in various cell types of the mouse ventral lumbar spinal cord, which is rich in motor neurons innervating the lower limb. To identify cell types affected by MG or ALS pathogenesis, we analyzed differentially expressed genes with known cell-type markers, which were determined from previous single-cell studies of the spinal cord in MG-exposed and SOD1 mice, an ALS mouse model. Differentially expressed genes were observed in MG mice in various spinal cord cell types, including neurons, microglia, astrocytes, oligodendrocytes, oligodendrocyte precursor cells, meningeal cells/Schwann cells, and vascular cells. We also examined neuronal populations in the spinal cord. Gene expression in putative excitatory and inhibitory neurons changed more than that in cholinergic motor neurons of the spinal cord in both MG and SOD1 mice. Many putative neuron types, especially visceral motor neurons, and axon initial segments (AIS) were affected in MG mice. In contrast, the effect on neurons and AIS in SOD1 mice was slight at P30 but progressed with aging. Interestingly, changes in dopaminergic system-related genes were specifically altered in the spinal cord of MG mice. These results indicate that MG and ALS pathology in various cell types contribute to motor neuron degeneration. Furthermore, there were more alterations in neurons in MG-exposed mice than in SOD1 mice. A large number of differentially expressed genes (DEGs) in MG mice represent more than SOD1 mice with ALS pathology. Elucidation of MG pathogenesis may provide more insight into the pathophysiology of neurodegenerative diseases.
微重力 (MG) 暴露和运动神经元疾病（如肌萎缩侧索硬化症 [ALS]）会导致运动功能障碍，包括肌肉萎缩和神经元活动丧失。MG 暴露引起的运动神经元和肌肉异常可以通过随后的地面运动来恢复。相比之下，ALS 中的退行性变是不可逆转的。MG 暴露和 ALS 病理学之间的一个共同表型是运动系统异常，但原因可能不同。在这项研究中，为了阐明受每种情况影响的运动系统，我们研究了 MG 和人类 SOD1 ALS 突变对小鼠腹侧腰椎脊髓各种细胞类型基因表达的影响，该脊髓富含支配下肢的运动神经元。为了确定受 MG 或 ALS 发病机制影响的细胞类型，我们分析了具有已知细胞类型标记物的差异表达基因，这些基因是从先前的 MG 暴露和 SOD1 小鼠（ALS 小鼠模型）脊髓单细胞研究中确定的。在 MG 小鼠的各种脊髓细胞类型中观察到差异表达基因，包括神经元、小胶质细胞、星形胶质细胞、少突胶质细胞、少突胶质细胞前体细胞、脑膜细胞/施万细胞和血管细胞。我们还检查了脊髓中的神经元群体。在 MG 和 SOD1 小鼠中，与脊髓中的胆碱能运动神经元相比，假定兴奋性和抑制性神经元的基因表达变化更大。在 MG 小鼠中，许多假定的神经元类型，尤其是内脏运动神经元和轴突起始段（AIS）受到影响。相比之下，SOD1 小鼠中神经元和 AIS 的影响在 P30 时较小，但随着年龄的增长而进展。有趣的是，MG 小鼠脊髓中多巴胺能系统相关基因的变化是特异性改变的。这些结果表明，MG 和各种细胞类型的 ALS 病理学导致运动神经元退化。此外，MG 暴露小鼠中的神经元变化比 SOD1 小鼠中的更明显。大量在 MG 小鼠中差异表达的基因（DEGs）比 SOD1 小鼠中的 ALS 病理学更多。阐明 MG 的发病机制可能会为神经退行性疾病的病理生理学提供更多的见解。
