Liu Hankui, Guan Liping, Deng Min, Bolund Lars, Kristiansen Karsten, Zhang Jianguo, Luo Yonglun, Zhang Zhanchi
Hebei Industrial Technology Research Institute of Genomics in Maternal and Child Health, BGI-Shijiazhuang Medical Laboratory, Shijiazhuang, China.
BGI-Shenzhen, Shenzhen, China.
Front Neurosci. 2023 Feb 17;17:1116087. doi: 10.3389/fnins.2023.1116087. eCollection 2023.
The gradual loss of motor neurons (MNs) in the brain and spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the mechanisms underlying neurodegeneration in ALS are still not fully understood.
Based on 75 ALS-pathogenicity/susceptibility genes and large-scale single-cell transcriptomes of human/mouse brain/spinal cord/muscle tissues, we performed an expression enrichment analysis to identify cells involved in ALS pathogenesis. Subsequently, we created a strictness measure to estimate the dosage requirement of ALS-related genes in linked cell types.
Remarkably, expression enrichment analysis showed that α- and γ-MNs, respectively, are associated with ALS-susceptibility genes and ALS-pathogenicity genes, revealing differences in biological processes between sporadic and familial ALS. In MNs, ALS-susceptibility genes exhibited high strictness, as well as the ALS-pathogenicity genes with known loss of function mechanism, indicating the main characteristic of ALS-susceptibility genes is dosage-sensitive and the loss of function mechanism of these genes may involve in sporadic ALS. In contrast, ALS-pathogenicity genes with gain of function mechanism exhibited low strictness. The significant difference of strictness between loss of function genes and gain of function genes provided a priori understanding for the pathogenesis of novel genes without an animal model. Besides MNs, we observed no statistical evidence for an association between muscle cells and ALS-related genes. This result may provide insight into the etiology that ALS is not within the domain of neuromuscular diseases. Moreover, we showed several cell types linked to other neurological diseases [i.e., spinocerebellar ataxia (SA), hereditary motor neuropathies (HMN)] and neuromuscular diseases [i.e. hereditary spastic paraplegia (SPG), spinal muscular atrophy (SMA)], including an association between Purkinje cells in brain and SA, an association between α-MNs in spinal cord and SA, an association between smooth muscle cells and SA, an association between oligodendrocyte and HMN, a suggestive association between γ-MNs and HMN, a suggestive association between mature skeletal muscle and HMN, an association between oligodendrocyte in brain and SPG, and no statistical evidence for an association between cell type and SMA.
These cellular similarities and differences deepened our understanding of the heterogeneous cellular basis of ALS, SA, HMN, SPG, and SMA.
脑和脊髓中运动神经元（MNs）的逐渐丧失是肌萎缩侧索硬化症（ALS）的一个标志，但ALS神经退行性变的潜在机制仍未完全了解。
基于75个ALS致病性/易感性基因以及人类/小鼠脑/脊髓/肌肉组织的大规模单细胞转录组，我们进行了表达富集分析，以确定参与ALS发病机制的细胞。随后，我们创建了一种严格性度量方法，以估计相关细胞类型中ALS相关基因的剂量需求。
值得注意的是，表达富集分析表明，α-运动神经元和γ-运动神经元分别与ALS易感性基因和ALS致病性基因相关，揭示了散发性和家族性ALS之间生物学过程的差异。在运动神经元中，ALS易感性基因表现出高严格性，以及具有已知功能丧失机制的ALS致病性基因，表明ALS易感性基因的主要特征是剂量敏感，这些基因的功能丧失机制可能与散发性ALS有关。相比之下，具有功能获得机制的ALS致病性基因表现出低严格性。功能丧失基因和功能获得基因之间严格性的显著差异为没有动物模型的新基因的发病机制提供了先验理解。除了运动神经元，我们没有观察到肌肉细胞与ALS相关基因之间存在关联的统计学证据。这一结果可能为ALS不属于神经肌肉疾病范畴的病因提供了见解。此外，我们展示了几种与其他神经系统疾病[即脊髓小脑共济失调（SA）、遗传性运动神经病（HMN）]和神经肌肉疾病[即遗传性痉挛性截瘫（SPG）、脊髓性肌萎缩症（SMA）]相关的细胞类型，包括脑内浦肯野细胞与SA之间的关联、脊髓中α-运动神经元与SA之间的关联、平滑肌细胞与SA之间的关联、少突胶质细胞与HMN之间的关联、γ-运动神经元与HMN之间的提示性关联、成熟骨骼肌与HMN之间的提示性关联、脑内少突胶质细胞与SPG之间的关联，以及没有细胞类型与SMA之间存在关联的统计学证据。
这些细胞的异同加深了我们对ALS、SA、HMN、SPG和SMA异质细胞基础的理解。
