Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University, P.O. Box 12272, 91120, Jerusalem, Israel.
The Sidney and Judy Swartz Embryonic Stem Cell Research Center of The Goldyne Savad Institute of Gene Therapy & The Department of Obstetrics, Hadassah University Medical Center, Jerusalem, 91120, Israel.
Cell Death Dis. 2018 Feb 15;9(3):256. doi: 10.1038/s41419-018-0294-6.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by cell death of upper and lower motor neurons (MNs). The cause of MN cell loss is not completely understood but involves both cell autonomous and non-cell autonomous mechanisms. Numerous molecules have been implicated to be involved in the death of MNs. One such candidate is semaphorin 3A (Sema3A). In ALS patients, Sema3A was shown to be significantly upregulated in the motor cortex and downregulated in the spinal cord. In the mouse, Sema3A was shown to be an axon repellent molecule for MNs. Sema3A could also induce death of different neuronal types that are also repelled by it, including sensory, sympathetic, retinal, and cortical neurons. In contrast, astrocyte-specific knockout of Sema3A results in motor neuron cell death, consistent with the idea that Sema3A is a survival factor for mouse motor neurons. Here, we tested the response of human cortical neurons and spinal cord MNs to Sema3A. We found that Sema3A enhances the survival of spinal cord MNs. In contrast, Sema3A reduces the survival of cortical neurons. Thus, both upregulation of Sema3A in the cortex, or downregulation in the spinal cord of ALS patients is likely to directly contribute to MNs cell loss in ALS patients.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是上下运动神经元（MNs）的细胞死亡。MN 细胞丢失的原因尚不完全清楚，但涉及自主和非自主细胞机制。许多分子被认为与 MN 细胞死亡有关。其中一个候选分子是神经突导向因子 3A（Sema3A）。在 ALS 患者中，Sema3A 在运动皮层中显著上调，而在脊髓中下调。在小鼠中，Sema3A 被证明是 MNs 的轴突排斥分子。Sema3A 还可以诱导不同神经元类型的死亡，这些神经元也被其排斥，包括感觉神经元、交感神经元、视网膜神经元和皮质神经元。相比之下，星形胶质细胞特异性敲除 Sema3A 会导致运动神经元死亡，这与 Sema3A 是小鼠运动神经元的存活因子的观点一致。在这里，我们测试了 Sema3A 对人皮质神经元和脊髓 MNs 的反应。我们发现 Sema3A 增强了脊髓 MNs 的存活。相比之下，Sema3A 减少了皮质神经元的存活。因此，ALS 患者皮层中 Sema3A 的上调或脊髓中 Sema3A 的下调都可能直接导致 MNs 细胞丢失。
